WO2017173302A2 - Inhibitors of integrin alpha 5 beta 1 and methods of use - Google Patents

Inhibitors of integrin alpha 5 beta 1 and methods of use Download PDF

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WO2017173302A2
WO2017173302A2 PCT/US2017/025432 US2017025432W WO2017173302A2 WO 2017173302 A2 WO2017173302 A2 WO 2017173302A2 US 2017025432 W US2017025432 W US 2017025432W WO 2017173302 A2 WO2017173302 A2 WO 2017173302A2
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substituted
unsubstituted
membered
heteroaryl
heteroalkyl
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PCT/US2017/025432
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French (fr)
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WO2017173302A3 (en
Inventor
Dean Sheppard
Aparna SUNDARAM
William F. Degrado
Hyunil JO
Joel Mcintosh
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The Regents Of The University Of California
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Priority to EP17776794.4A priority Critical patent/EP3436046A4/en
Priority to US16/090,022 priority patent/US10836720B2/en
Priority to CA3019130A priority patent/CA3019130A1/en
Publication of WO2017173302A2 publication Critical patent/WO2017173302A2/en
Publication of WO2017173302A3 publication Critical patent/WO2017173302A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • R 1 is independently halogen, - -SO iR 1D ,
  • L 1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , - CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2, -CN, -SO ⁇ R 20 ,
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety.
  • R 4 is independently hydrogen, -CX 4 3 , -CN, -COOH, -CONH 2 , -CHX 4 2 , -CH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • L 2 is unsubstituted alkylene.
  • L 3 is a bond, -0-, -S-, - N(R 7 )-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • L 4 is -0-, -S-,-N(R 8 )-, -C(O)-, C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene.
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 5 and R 6 are
  • R 5 and R 6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 9 is hydrogen, halogen, -N 3 , -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , -CN, -CHO, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, - S0 2 , -S0 2 CH 3 -S0 3 H, -SO 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 10 is hydrogen, halogen, -N 3 , -CX 10 3 , -CHX 10 2 , - CH 2 X 10 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC (0)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Each X, X 1 , X 2 , X 4 , X 7 , X 8 , X 9 , and X 10 are independently -F, -CI, -Br, or -I.
  • the symbols nl and n2 are independently an integer from 0 to 4.
  • the symbols ml, m2, vl and v2 are independently 1 or 2.
  • zl is an integer from 0 and 5.
  • z2 is an integer from 0 and 9.
  • z3 is 0 or 1. In embodiments, when R 5 is hydrogen, R 6 is not hydrogen.
  • composition including a
  • a method for treating asthma including
  • R 1 is independently halogen, , -SO iR 1D ,
  • L 1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -CN, -SO ⁇ R 20 , -SO v2 R 2A R 2B ,
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety.
  • R 4 is independently
  • L 2 is unsubstituted alkylene.
  • L 3 is a bond, -0-, -S-, -N(R 7 )-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • L 4 is -0-, -S- - N(R 8 )-, -C(O)-, C(0)0- -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene.
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 5 and R 6 are independently hydrogen, , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 and R 6 may optionally be joined to form a substituted or unsubstituted
  • R 9 is hydrogen, halogen, -N 3 , -CX 9 3 , -CHX 9 2, -CH 2 X 9 , -CN, -CHO, -OH, -NH 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -SO 4 H, -S0 2 H 2 , - HNH 2 , -O H 2 , - HC(0) H H 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 10 is hydrogen, halogen, -N 3 , -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -CN, -CHO, -OH, -NH 2 , - COOH, -CONH 2 , -N0 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(0)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D is independently hydrogen, -CX 3 , -CN, -COOH, -CONH 2 , -CHX 2 , -CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Each X, ⁇ 1, ⁇ 2, ⁇ 4, ⁇ 7, ⁇ 8, ⁇ 9, and X 10 are independently -F, -CI, -Br, or -I.
  • nl and n2 are independently an integer from 0 to 4.
  • the symbols ml, m2, vl and v2 are independently 1 or 2.
  • zl is an integer from 0 and 5.
  • z2 is an integer from 0 and 9.
  • z3 is 0 or l .
  • a method of treating cancer including administering to a subject in need thereof an effective amount of a compound, or pharmaceutically acceptable salt, as described herein.
  • a method of treating an inflammatory disease including administering to a subject in need thereof an effective amount of a compound, or
  • a method of treating an autoimmune disease including administering to a subject in need thereof an effective amount of a compound, or
  • a method of detecting the presence of ⁇ 5 ⁇ 1 integrin or inhibiting ⁇ 5 ⁇ 1 integrin activity including contacting an ⁇ 5 ⁇ 1 integrin with a compound, or pharmaceutically acceptable salt, as described herein.
  • FIGS. 1A-1B To investigate the role of ⁇ 5 ⁇ 1 integrin in smooth muscle, wildtype (WT) mice were sensitized and challenged with ovalbumin (OVA). After intranasal
  • Integrins are present in nearly all multi-cellular organisms and play a conserved role in mediating cell adhesion to fixed extracellular ligands and in the maintenance of tissue integrity. In invertebrates, a surprisingly small number of integrin heterodimers mediate these diverse functions. Much has been learned about the critical in vivo functions of most members of the integrin family through the use of mice with global or conditional inactivating mutations of individual subunits and through the use of heterodimer-specific blocking monoclonal antibodies. Pharmacological modulation of the ⁇ 5 ⁇ 1 integrin by compounds described herein may be used to treat asthma. Described herein are compounds and methods of use for ⁇ 5 ⁇ 1 integrin inhibitors.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkyl moiety may be fully saturated.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited
  • alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched non-cyclic chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., O, N, P, S, or Si
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 - H-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0) R', -NR'R", -OR, -SR, and/or -S0 2 R.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
  • cycloalkyl and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of “alkyl” and
  • heteroalkyl respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non- hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-l,2, dione, adamantanyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • a heterocycloalkyl moiety may include one ring heteroatom (e.g., O, N, S, Si, or P).
  • a heterocycloalkyl moiety may include two optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
  • a heterocycloalkyl moiety may include three optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
  • a heterocycloalkyl moiety may include four optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
  • a heterocycloalkyl moiety may include five optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
  • a heterocycloalkyl moiety may include up to 8 optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4- biphenyl, 1 -pyrrol yl, 2-pyrrolyl, 3 -pyrrol yl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indoly
  • aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • Non-limiting examples of aryl and heteroaryl groups include pyridinyl,
  • a heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S).
  • a heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S).
  • a heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S).
  • An aryl moiety may have a single ring.
  • An aryl moiety may have two optionally different rings.
  • An aryl moiety may have three optionally different rings.
  • An aryl moiety may have four optionally different rings.
  • a heteroaryl moiety may have one ring.
  • a heteroaryl moiety may have two optionally different rings.
  • a heteroaryl moiety may have three optionally different rings.
  • a heteroaryl moiety may have four optionally different rings.
  • a heteroaryl moiety may have five optionally different rings.
  • a fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl.
  • a fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl.
  • heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.
  • heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl.
  • Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.
  • oxo as used herein, means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(0 2 )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R may have a specified number of carbons (e.g., "C 1 -C 4 alkylsulfonyl").
  • R, R, R", R", and R" each preferably
  • each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present.
  • R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • substituents for the aryl and heteroaryl groups are varied and are selected from, for
  • R'C (0) R" R'"R"", -CN, -N0 2 , -R, -N 3 , -CH(Ph) 2 , fluoro(Ci-C 4 )alkoxy, and fluoro(Ci- C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present.
  • substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring- forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR) q -U-, wherein T and U are
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR-, -0-, - R-, -S-, -S(O) -, -S(0) 2 -, -S(0) 2 R'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the
  • R, R, R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or “ring heteroatom” are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a "substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF 3 , -CN, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -S0 3 H, -S0 4 H, -
  • heterocycloalkyl unsubstituted aryl, unsubstituted heteroaryl, and
  • a "size-limited substituent” or " size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl, and each substituted or unsubstituted heteroaryl is
  • a "lower substituent” or " lower substituent group,” as used herein, means a group selected from all of the substituents described above for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or un
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -Ci 0 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -Cio aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C 8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -Ci 0 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
  • the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids.
  • the present invention includes such salts.
  • examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • agents e.g. compounds, drugs, therapeutic agents
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents). Additionally, prodrugs can be converted to agents (e.g. compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment.
  • Prodrugs described herein include compounds that readily undergo chemical changes under select physiological conditions to provide agents (e.g. compounds, drugs, therapeutic agents) to a biological system (e.g. in a subject, in a cancer cell, in the extracellular space near a cancer cell).
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • salt refers to acid or base salts of the compounds used in the methods of the present invention.
  • Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute
  • stereochemistry as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • a or “an,” as used herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted Ci-C 2 o alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R- substituted where a moiety is substituted with an R substituent, the group may be referred to as "R- substituted.” Where a moiety is R- substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
  • a "detectable moiety” as used herein refers to a moiety that can be covalently or noncovalently attached to a compound or biomolecule that can be detected for instance, using techniques known in the art.
  • the detectable moiety is covalently attached.
  • the detectable moiety may provide for imaging of the attached compound or biomolecule.
  • the detectable moiety may indicate the contacting between two compounds.
  • Exemplary detectable moieties are fluorophores, antibodies, reactive dies, radio-labeled moieties, magnetic contrast agents, and quantum dots.
  • Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes.
  • Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64.
  • Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese.
  • the detectable moiety may be covalently attached through a covalent linker to the remainder of the molecule, wherein the covalent linker forms part of the detectable moiety. Therefore, a detectable moiety may include a detectable portions (e.g. a fluorophore) and covalent linker portion.
  • the covalent linker portion may be L 12 , wherein L 12 is -0-, -C(O)-, -CO(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene.
  • the covalent linker portion may be L 12 , wherein L 12 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
  • preparation is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • an " ⁇ 5 ⁇ 1 -inhibitor” as used herein refers to a composition (e.g. a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) capable of reducing the activity of ⁇ 5 ⁇ 1 integrin when compared to a control compound (e.g. known to have no reduction in ⁇ 5 ⁇ 1 integrin activity) or the absence of the ⁇ 5 ⁇ 1 -inhibitor compound.
  • a control compound e.g. known to have no reduction in ⁇ 5 ⁇ 1 integrin activity
  • ⁇ 5 ⁇ 1 -inhibitor compound refers to a compound (e.g. compounds described herein) that reduce the activity of ⁇ 5 ⁇ 1 integrin when compared to a control, such as absence of the compound or a compound with known inactivity.
  • ⁇ 5 ⁇ 1 -inhibitor-antibody refers to an antibody that reduces the activity of ⁇ 5 ⁇ 1 integrin when compared to a control (e.g. the absence of the antibody).
  • a5pi-inhibitor-RGD peptide refers to a RGD-peptide that reduces the activity of ⁇ 5 ⁇ 1 integrin when compared to a control (e.g. the absence of the peptide).
  • An " ⁇ 5 ⁇ 1 -specific moiety", “specific,” “specifically”, “specificity”, or the like of a composition e.g.
  • a compound, nucleic acid, polynucleotide, peptide, protein, or antibody refers to the composition's ability to discriminate between particular molecular targets to a significantly greater extent than other proteins in the cell (e.g. a compound having specificity towards ⁇ 5 ⁇ 1 integrin binds to ⁇ 5 ⁇ 1 integrin whereas the same compound displays little-to-no binding to other integrins such as ⁇ , ⁇ 8 ⁇ 1, ⁇ 2 ⁇ 1, ⁇ 3, ⁇ 5, or ⁇ ).
  • An " ⁇ 5 ⁇ 1 -specific compound” refers to a compound (e.g. compounds described herein) having specificity towards ⁇ 5 ⁇ 1 integrin.
  • ⁇ 5 ⁇ 1 -specific antibody refers to an antibody having specificity towards ⁇ 5 ⁇ 1 integrin.
  • ⁇ 5 ⁇ 1 -specific RGD peptide refers to a RGD peptide having specificity towards ⁇ 5 ⁇ 1 integrin.
  • ⁇ 5 ⁇ 1 -selective refers to the composition's (e.g. a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) ability to cause a particular action in a particular molecular target (e.g. a compound having selectivity toward ⁇ 5 ⁇ 1 integrin would inhibit only ⁇ 5 ⁇ 1).
  • ⁇ 5 ⁇ 1 -selective compound refers to a compound (e.g. compounds described herein) having selectivity towards ⁇ 5 ⁇ 1 integrin.
  • ⁇ 5 ⁇ 1 -selective antibody refers to an antibody having selectivity towards ⁇ 5 ⁇ 1 integrin.
  • ⁇ 5 ⁇ 1 -selective RGD peptide refers to a RGD peptide having selectivity towards ⁇ 5 ⁇ 1 integrin.
  • polypeptide peptide
  • protein protein
  • amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
  • a polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type).
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is
  • RGD peptide refers to a tripeptide comprising Arg, Gly, and Asp. RGD peptides typically act as recognition sequences for integrins and in some embodiments, promote cellular adhesion via integrin binding. RGD peptides as used herein refers to naturally occurring RGD sequences, RGD mimetics (e.g. substitutions of R, G, or D with non- proteinogenic amino acids), RGD peptides covalently bound to a targeting-moiety (e.g. a molecule for targeting the peptide to a specific integrin or specific location in a cell or organism), and cyclized RGD peptides of embodiments described herein.
  • a targeting-moiety e.g. a molecule for targeting the peptide to a specific integrin or specific location in a cell or organism
  • RGD peptides include Arg-Gly-Asp, Asp-Gly-Arg, cyclo-Gly-Arg-Gly-Asp-Ser-Pro, and KGD peptides include Cys- Asn-Thr-Leu-Lys-Gly-Asp-Cys and Asn-Thr-Leu-Lys-Gly-Asp, and those found in Ann. Rev. Cell & Dev. Biol., 1996, Nov., Vol. 12: 697-715 and Proteins, 1992 Dec; 14(4):509-15.
  • Antibody refers to a polypeptide comprising a framework region from an
  • immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • the antigen-binding region of an antibody will be most critical in specificity and affinity of binding.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kD) and one "heavy” chain (about 50-70 kD).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms variable light chain (V L ) and variable heavy chain (V H ) refer to these light and heavy chains respectively.
  • Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases.
  • pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)' 2; a dimer of Fab which itself is a light chain joined to V H -C H 1 by a disulfide bond.
  • the F(ab)' 2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)' 2 dimer into an Fab' monomer.
  • the Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using
  • the genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybndoma and used to produce a recombinant monoclonal antibody.
  • Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybndoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby,
  • phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al, Nature 348:552-554 (1990); Marks et al, Biotechnology 10:779-783 (1992)).
  • Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al, EMBO J. 10:3655-3659 (1991); and Suresh et al, Methods in Enzymology 121 :210 (1986)).
  • Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Jones et al, Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988); Verhoeyen et al, Science 239: 1534-1536 (1988) and Presta, Curr. Op. Struct. Biol.
  • humanized antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • a "chimeric antibody” is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.
  • the preferred antibodies of, and for use according to the invention include humanized and/or chimeric monoclonal antibodies.
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including
  • the term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.
  • activation As defined herein, the term “activation”, “activate”, “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state.
  • the terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
  • the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • inhibition refers means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor.
  • inhibition refers to reduction of a disease or symptoms of disease.
  • inhibition refers to a reduction in the activity of a particular protein target.
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein).
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
  • Patient or “subject in need thereof or “subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method, as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • a subject is human.
  • Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein.
  • the disease is asthma.
  • the disease may be airway
  • the disease may be airway hyperresponsiveness in asthma.
  • the disease may be angiogenesis.
  • the disease may be a cancer (e.g., ovarian cancer, bladder cancer, head and neck cancer, brain cancer, breast cancer, lung cancer, cervical cancer, liver cancer, colorectal cancer, pancreatic cancer, glioblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, renal cancer, renal cell carcinoma, non-small cell lung cancer, uterine cancer, testicular cancer, anal cancer, bile duct cancer, biliary tract cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, urinary bladder cancer, genitourinary tract cancer, endometrial cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, or prostate cancer).
  • the disease may be an anal cancer, bile duct cancer, bil
  • autoimmune disease e.g., scleroderma, lupus, diabetes, or rheumatoid arthritis.
  • the disease may be an inflammatory disease (e.g., autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto' s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet' s disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory
  • cancer refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin' s lymphomas (e.g., Burkitt' s, Small Cell, and Large Cell lymphomas), Hodgkin' s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
  • cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc. including solid and lymphoid cancers, kidney, breast, lung, bladder
  • inflammatory disease refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease).
  • inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren' s
  • vasculitis vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet' s disease, Crohn' s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison' s disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemia, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include breast cancer (e.g. ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g.
  • non-small cell lung carcinoma squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma.
  • Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, acral- lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,
  • bronchogenic carcinoma cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair- matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare,
  • aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • a "effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition).
  • An example of an "effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques ⁇ see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.).
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
  • therapeutically effective amounts for use in humans can also be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated.
  • administering means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation.
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be coadministered to the patient.
  • Coadministration is meant to include simultaneous or sequential administration of the
  • compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • a "cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaroytic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • Control or "control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.
  • the control is used as a standard of comparison in evaluating experimental effects.
  • a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
  • compositions provided by the present invention include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
  • Such compositions When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of asthma). Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.
  • asthma refers to any disease or condition characterized by inflammation within the circulatory system, often accompanied with wheezing, airway restriction, shortness of breath, chest tightness, and coughing.
  • wheezing airway restriction
  • shortness of breath characterized by wheezing
  • chest tightness characterized by wheezing
  • coughing characterized by wheezing, airway restriction, shortness of breath, chest tightness, and coughing.
  • asthma is characterized by airway hyperresponsiveness.
  • asthma is airway
  • Asthma may refer inflammation in the bronchi and bronchioles. Asthma may refer to atopic asthma. Asthma may refer to non-atopic asthma.
  • the compounds described herein may be prodrugs.
  • prodrug when referring to a prodrug described herein (e.g. ⁇ 5 ⁇ 1 -inhibitor compound moiety bonded to a prodrug moiety) refers to the compound including the ⁇ 5 ⁇ 1- inhibitor compound moiety and the prodrug moiety.
  • prodrug moiety is the portion of a prodrug that may be cleaved from the prodrug resulting in an increased activity of the non- prodrug moiety portion of the prodrug, for example an ⁇ 5 ⁇ 1 -inhibitor compound having increased ⁇ 5 ⁇ 1 -inhibitor activity relative to the prodrug of the ⁇ 5 ⁇ 1 -inhibitor compound.
  • the compounds described herein are prodrugs, wherein the prodrug moiety is the component of the compound that is not an ⁇ 5 ⁇ 1 -inhibitor compound moiety and is released from the ⁇ 5 ⁇ 1 -inhibitor compound moiety upon degradation of the prodrug.
  • degradation of the prodrug includes cleavage of -OR 3 , wherein R 3 is not hydrogen. In embodiments, degradation of the prodrug includes cleavage of -R 3 , wherein R 3 is not hydrogen.
  • an ⁇ 5 ⁇ 1 -inhibitor compound is a compound described herein wherein R 3 is hydrogen and a prodrug of the ⁇ 5 ⁇ 1 -inhibitor compound is the identical compound except R 3 is not a hydrogen.
  • the ⁇ 5 ⁇ 1 -inhibitor compound moiety includes only those compounds compatible with the chemistry provided herein for connecting the ⁇ 5 ⁇ 1 -inhibitor compound moiety to the prodrug moiety and for release of the ⁇ 5 ⁇ 1 -inhibitor compound from the compound (prodrug) (e.g., in vivo).
  • degradation of the prodrug releases an active agent (e.g., ⁇ 5 ⁇ 1 -inhibitor compound).
  • the resulting active agent includes a higher level of activity compared to the level of activity of the intact prodrug.
  • Integrins are transmembrane proteins that mediate interactions between adhesion molecules on adjacent cells and/or the extracellular matrix (ECM). Integrins have diverse roles in several biological processes including, for example, cell migration during development and wound healing, cell differentiation, and apoptosis. Integrins typically exist as heterodimers consisting of a subunits (about 120-170 kDa in size) and ⁇ subunits (about 90-100 kDa in size). [0097] The terms " ⁇ 5 ⁇ ' and " ⁇ 5 ⁇ 1 integrin” refer to an integrin comprised of a5 subunit and a ⁇ ⁇ subunit and is used according to its common, ordinary meaning.
  • ⁇ 5 ⁇ ' refers to proteins of the same or similar names, homologs, isoforms, and functional fragments thereof, so long as such fragments retain ⁇ 5 ⁇ 1 integrin activity.
  • the term includes any recombinant or naturally- occurring form of ⁇ 5 ⁇ 1, or an ⁇ 5 ⁇ 1 preprotein, or variants thereof that maintain ⁇ 5 ⁇ 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype ⁇ 5 ⁇ 1).
  • a5 has the protein sequence corresponding to RefSeq
  • a5 has the protein sequence corresponding to the proteolytically processed mature version of RefSeq NP_002196.3. In embodiments, a5 has the amino acid sequence corresponding to the reference number GI: 93814881 1. In embodiments, ⁇ has the protein sequence corresponding to RefSeq P 002202.2 In embodiments, ⁇ ⁇ has the amino acid sequence corresponding to the reference number GI: 19743813.
  • R 1 is independently halogen, -
  • L 1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , - CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 ,
  • R 2D -SO v2 NR 2A R 2B , -NHC (0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C(0)R 2C , -C(0)-OR 2C , -C(0)NR 2A R 2B , -OR 2D , -NR 2A S0 2 R 2D , -NR 2A C(0)R 2C , -NR 2A C(0)OR 2C , -NR 2A OR 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted alkyl, substituted or un
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R 4 is independently hydrogen, -CX 4 3 , -CN,
  • L is unsubstituted alkylene.
  • L 3 is a bond, -0-, -S-, -N(R 7 )-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroaryl ene.
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • L 4 is -0-, -S-,-N(R 8 )-, - C(O)-, C(0)0-, -S(O) -, -S(0) 2 - substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 5 and R 6 are independently hydrogen,
  • R 5 and R 6 may optionally be joined to form a substituted or unsubstituted
  • R 9 is hydrogen, halogen, -N 3 , -CX 9 3 , -CHX 9 2 , -CH2X 9 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 10 is hydrogen, halogen, -N 3 , -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -CN, -CHO, -OH, -NH 2 , - COOH, -CONH2, -NO2, -SH, -SO2, -S0 2 CH 3 -S0 3 H, -SO4H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , - NHC(0)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Each X, X 1 , X 2 , X 4 , X 7 , X 8 , X 9 , and X 10 are independently -F, -CI, -Br, or -I.
  • the symbols nl and n2 are independently an integer from 0 to 4.
  • the symbols ml, m2, vl and v2 are independently 1 or 2.
  • zl is an integer from 0 and 5.
  • z2 is an integer from 0 and 9.
  • z3 is 0 or 1.
  • Y is -C-C-.
  • Y is -0-C-.
  • Y is -C-0-.
  • Y is -C-0-C-.
  • Y is -C-S-.
  • Y is -S-C-.
  • Y is -C-S-C-. 0101]
  • the compound has the formula:
  • R 1 is independently halogen, -N 3 , -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CN, -
  • R 1 is independently halogen, -N 3 , -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , - CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -OS0 3 H, -S0 2 NH 2 , - NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , substituted or unsubstituted alkyl, substituted or
  • R 1 is independently halogen, -OMe, -SMe, -S0 2 Me, -S0 2 Ph, -COOH, substituted or unsubstituted Ci-C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 1 is R 11 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), R u -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R u -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • R u -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered
  • R 11 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11 -substituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 11 - substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1 is R 11 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl), R 11 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11 -substituted cycloalkyl (e.g.
  • R u -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R u -substituted aryl e.g. C 6 - C10 aryl or C 6 aryl
  • R 11 -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • unsubstituted alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Cio aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 12 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 12 -substituted or unsubstituted cycloalkyl (e.g.
  • R 12 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 12 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 12 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 11 is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 13 - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C5-C6 cycloalkyl
  • R 13 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 13 - substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 13 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 12 is a halogen.
  • R 1 is independently halogen, -CX l 3 , -OCX l 3 , - OCH 2 X 1 , -OCHX ⁇ , -CN, -SO definitionR 1D , -SO v iNR 1A R 1B , -NHC(0)NR 1A R 1B , -N(0) mi , -NR 1A R 1B , -C( 0)R 1C , -C(0)-OR lc , -C(0)NR 1A R 1B , -OR 1D , -NR 1A S0 2 R 1D , -NR 1A C(0)R 1C , -NR 1A C(0)OR lc , or -NR 1A OR lc .
  • R 1A is R 11A -substituted or unsubstituted alkyl (e.g. C C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 11A -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11A -substituted or unsubstituted cycloalkyl (e.g.
  • R 11A -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11A -substituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 11A -substituted or unsubstituted heteroaryl e.g.
  • R 1A is -CX 1A 3, -CN, -COOH, -C(0) H 2 , R 11A -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci- C 4 alkyl), R 11A -substituted heteroalkyl (e.g.
  • R 11A -substituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 11A -substituted heterocycloalkyl e.g.
  • R 11A -substituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 11A -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • R 1A is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 1A is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 12A - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 12A -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 12A -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 12A -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 11A is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 13A - substituted or unsubstituted cycloalkyl e.g. C3-C 8 cycloalkyl, C4-C 8 cycloalkyl, or C5-C6 cycloalkyl
  • R 13A -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 13A -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 13A -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 12A is a halogen.
  • R 1B is R 11B -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 11B -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11B -substituted or unsubstituted cycloalkyl (e.g.
  • R 11B -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11B -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 11B -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1B is -CX 1B 3 , -CN, -COOH, -C(0) H 2 , R 11B -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 11B -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11B -substituted cycloalkyl (e.g.
  • R 11B -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11B -substituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 11B -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1B is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • X 1B is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 12B -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 12B - substituted or unsubstituted cycloalkyl (e.g.
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 11B is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 13B -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 13B - substituted or unsubstituted cycloalkyl (e.g.
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R is R -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 lie
  • R -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R lie -substituted or unsubstituted cycloalkyl e.g.
  • R -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 lie
  • R -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 lie
  • aryl e.g., aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1C is -CX 1C 3 , -CN, -COOH, -C(0)NH 2 , R 11C - substituted alkyl (e.g.
  • R -substituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R lie -substituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, l ie
  • R -substituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g.
  • unsubstituted alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • unsubstituted heteroalkyl e.g. 2 to 10 membered
  • X is a halogen
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 1 IC is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C4-C 8 cycloalkyl, or C5-C6 cycloalkyl
  • R -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X is a halogen.
  • R 1D is R 11D -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 11D -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11D -substituted or unsubstituted cycloalkyl (e.g.
  • R 11D -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11D -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 11D -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1D is -CX 1D 3 , -CN, -COOH, -C(0) H 2 , R 11D -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 11D -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 11D -substituted cycloalkyl (e.g.
  • R 11D -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 11D -substituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 11D -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 1D is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • X 1D is a halogen.
  • R 11D is independently hydrogen, halogen, -CX 11D 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 ,
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to
  • R 12D substituted or unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 12D -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
  • R -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 11D is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 13D - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 13D -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 12D is a halogen.
  • R 2 is R 14 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 14 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered hetero
  • R 14 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 14 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2 is R 14 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14 -substituted cycloalkyl (e.g.
  • R 14 -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14 -substituted aryl e.g. C 6 -
  • R 2 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Cio aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl R 15 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 15 -substituted or unsubstituted cycloalkyl (e.g.
  • R 15 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 15 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 15 -substituted or unsubstituted heteroaryl e.g.
  • X 14 is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl R 16 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 16 -substituted or unsubstituted cycloalkyl (e.g.
  • R 16 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 16 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 16 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 15 is a halogen.
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , - OCH 2 X 2 , -OCHX 2 2, -CN, -SO Rule2R 2D , -SO v2 NR 2A R 2B , -NHC(0)NR 2A R 2B , -N(0) m2 , -NR 2A R 2B , -C( 0)R 2C , -C(0)-OR 2C , -C(0) R 2A R 2B , -OR 2D , - R 2A S0 2 R 2D , - R 2A C(0)R 2C , - R 2A C(0)OR 2C , or - R 2A OR 2C .
  • R 2A is R 14A -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl), R 14A -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14A -substituted or unsubstituted cycloalkyl (e.g.
  • R 14A -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14A -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 14A -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 2 is a halogen.
  • R 2A is -CX 2A 3 , -CN, -COOH, -C(0) H 2 , R 14A -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14A -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14A -substituted cycloalkyl (e.g.
  • R 14A -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14A -substituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 14A -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2A is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • X 2A is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 15A - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 15A -substituted or unsubstituted heterocycloalkyl e.g.
  • R 15A -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 15A -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 14A is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 16A - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 16A -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 16A -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 16A -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 15A is a halogen.
  • R 2B is R 14B -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14B -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14B -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 14B -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to
  • R 14B -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14B -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 14B -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 2B is -CX 2B 3 , -CN, -COOH, -C(0)NH 2 , R 14B -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14B -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14B -substituted cycloalkyl (e.g.
  • R 14B substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
  • R -substituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • R 2B is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g.
  • cycloalkyl
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 15B - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 15B -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 15B -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 15B -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 14B is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 16B - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 16B -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • R 16B -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 16B -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 15B is a halogen.
  • R is R -substituted or unsubstituted alkyl (e.g.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R -substituted or unsubstituted cycloalkyl (e.g.
  • R -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g.
  • R 2C is -CX 2C 3 , -CN, -COOH, -C(0) H 2 , R 14C -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R -substituted heteroalkyl (e.g.
  • R -substituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted aryl e.g.
  • R is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g.
  • X is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C5-C6 cycloalkyl
  • R -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 16C -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 16C - substituted or unsubstituted cycloalkyl (e.g.
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 16C -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 16C -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X is a halogen.
  • R 2D is R 14D -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14D -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 14D -substituted or unsubstituted cycloalkyl (e.g.
  • R 14D -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14D -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 14D -substituted or unsubstituted heteroaryl e.g.
  • R 2D is -CX 2D 3 , -CN, -COOH, -C(0)NH 2 , R 14D -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 14D -substituted heteroalkyl (e.g.
  • R 14D -substituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 14D -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 14D -substituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 14D -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • R 2D is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g.
  • X 2D is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 15D - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 15D -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 15D -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 15D -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 14D is a halogen.
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 16D - substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 16D -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 16D -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 16D -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 15D is a halogen.
  • R 3 is R 17 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl), R 17 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 17 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl
  • R 17 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered hetero
  • R 17 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 17 -substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 17 -substituted or unsubstituted heteroaryl e.g.
  • R 3 is hydrogen. In embodiments, R 3 is an unsubstituted C 1 -C 4 alkyl.
  • R 3 may be substituted or unsubstituted alkyl.
  • R 3 may be substituted or unsubstituted heteroalkyl.
  • R 3 may be substituted or unsubstituted cycloalkyl.
  • R 3 may be substituted or unsubstituted heterocycloalkyl.
  • R 3 may be substituted or unsubstituted aryl.
  • R 3 may be substituted or unsubstituted heteroaryl.
  • R 3 is an unsubstituted methyl.
  • R 3 is an unsubstituted ethyl.
  • R 3 is an unsubstituted propyl.
  • R 3 is an unsubstituted isopropyl.
  • R 3 is an unsubstituted t-butyl. In embodiments, R 3 is an unsubstituted butyl. In embodiments, R 3 is an unsubstituted Ci-C 6 alkyl. In embodiments, R 3 is a substituted methyl. In embodiments, R 3 is a substituted ethyl. In embodiments, R 3 is a substituted propyl. In embodiments, R 3 is a substituted isopropyl. In embodiments, R 3 is a substituted t-butyl. In embodiments, R 3 is a substituted butyl. In embodiments, R 3 is a substituted Ci-C 6 alkyl.
  • -OR 3 is a prodrug moiety.
  • R 3 is a prodrug moiety. It will be understood that when R 3 is a prodrug moiety, the reaction that removes the prodrug moiety from the remainder of a compound described herein (e.g., prodrug) may, in embodiments, also remove the oxygen directly connected to R 3 . In embodiments, where -OR 3 is removed, an - OH may replace the -OR 3 .
  • R 4 is R 18 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 18 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 18 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 18 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered hetero
  • R 18 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 18 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 18 -substituted or unsubstituted heteroaryl e.g.
  • R 4 is hydrogen.
  • R 4 is R 18 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl).
  • R 5 is hydrogen, , or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is hydrogen. In embodiments, R 5 is hydrogen, , substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5 is a substituted or
  • R 5 is hydrogen
  • R 5 is R 19 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 19 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 19 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 19 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered hetero
  • R 19 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 19 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 19 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 5 is R 19 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), R 19 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 19 -substituted cycloalkyl (e.g.
  • R -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R -substituted aryl e 6"
  • R 5 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Ci 0 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 20 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 20 -substituted or unsubstituted cycloalkyl (e.g.
  • R 20 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 20 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 20 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 19 is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 21 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 21 - substituted or unsubstituted cycloalkyl (e.g.
  • R 21 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 21 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 21 - substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 20 is a halogen.
  • R 6 is hydrogen. In embodiments, R 6 is hydrogen, , or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 6 is hydrogen, , substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 6 is a substituted or nsubstituted 5 to 6 membered heteroaryl.
  • R 6 is hydrogen
  • R 5 is hydrogen and R 6 is , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is hydrogen
  • R 6 is , substituted or unsubstituted alkyl
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g.
  • R 5 is hydrogen and R 6 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
  • R 5 is hydrogen and R 6 is , substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci- C 4 alkyl), substituted or unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 - C 6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
  • heterocycloalkyl 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 5 and R 6 are joined to form a substituted or unsubstituted
  • R 5 and R 6 are joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form a substituted 4 to 8 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form a substituted 5 to 6 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form a substituted 5 membered heterocycloalkyl.
  • R 5 and R 6 are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 6 membered heterocycloalkyl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 5 membered heterocycloalkyl.
  • R 5 and R 6 are joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form a substituted 5 to 9 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form a substituted 5 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form a substituted 6 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 5 to 10 membered heteroaryl.
  • R 5 and R 6 are joined to form an unsubstituted 5 to 9 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 5 membered heteroaryl. In embodiments, R 5 and R 6 are joined to form an unsubstituted 6 membered heteroaryl.
  • R 5 is hydrogen and R 6 . In embodiments, R 5 is
  • R 5 is hydrogen and R 6 .
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted 5 to 10 membered heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted 5 to 6 membered heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted 5 membered heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 5 is hydrogen and R 6 is a substituted 5 membered heteroaryl. In embodiments, R 5 is hydrogen and R 6 is a substituted 6 membered heteroaryl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted 5 membered heteroaryl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted 6 membered heteroaryl.
  • R 5 is hydrogen and R 6 is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyranyl, substituted or unsubstituted thiopyranyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimindyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazinyl, substituted or unsubstituted thiazinyl, substituted or
  • R 5 is hydrogen and R 6 is phenyl. In embodiments, R 5 is hydrogen and R 6 is a substituted phenyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted phenyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted triazolyl. In
  • R 5 is hydrogen and R 6 is a substituted triazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted triazolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted tetrazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted tetrazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted tetrazolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyridinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyridinyl.
  • R 5 is hydrogen and R 6 is an unsubstituted pyridinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyrrolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyrrolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted pyrrolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted furanyl. In embodiments, R 5 is hydrogen and R 6 is a substituted furanyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted furanyl.
  • R 5 is hydrogen and R 6 is substituted or unsubstituted thiophenyl. In embodiments, R 5 is hydrogen and R 6 is a substituted thiophenyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted thiophenyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted imidazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted imidazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted imidazolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyrazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyrazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted pyrazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyrazolyl. In embodiments, R 5 is hydrogen and R 6
  • R 5 is hydrogen and R 6 is substituted or unsubstituted oxazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted oxazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted oxazolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted thiazolyl. In embodiments, R 5 is hydrogen and R 6 is a substituted thiazolyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted thiazolyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyranyl.
  • R 5 is hydrogen and R 6 is a substituted pyranyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted pyranyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted thiopyranyl. In embodiments, R 5 is hydrogen and R 6 is a substituted thiopyranyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted thiopyranyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyrazinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyrazinyl.
  • R 5 is hydrogen and R 6 is an unsubstituted pyrazinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyrimindyl. In embodiments, R 5 is hydrogen and R 6 is a substituted pyrimindyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted pyrimindyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted pyridazinyl. In
  • R 5 is hydrogen and R 6 is a substituted pyridazinyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted pyridazinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted oxazinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted oxazinyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted oxazinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted thiazinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted thiazinyl.
  • R 5 is hydrogen and R 6 is an unsubstituted thiazinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted doxinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted doxinyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted doxinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted dithiinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted dithiinyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted dithiinyl.
  • R 5 is hydrogen and R 6 is substituted or unsubstituted azetyl. In embodiments, R 5 is hydrogen and R 6 is a substituted azetyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted azetyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted oxetyl. In embodiments, R 5 is hydrogen and R 6 is a substituted oxetyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted oxetyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted thietyl.
  • R 5 is hydrogen and R 6 is a substituted thietyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted thietyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted azirinyl. In embodiments, R 5 is hydrogen and R 6 is a substituted azirinyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted azirinyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted oxirenyl. In embodiments, R 5 is hydrogen and R 6 is a substituted oxirenyl.
  • R 5 is hydrogen and R 6 is an unsubstituted oxirenyl. In embodiments, R 5 is hydrogen and R 6 is substituted or unsubstituted thienyl. In embodiments, R 5 is hydrogen and R 6 is a substituted thienyl. In embodiments, R 5 is hydrogen and R 6 is an unsubstituted thienyl. [0160] In embodiments, R 6 is R 22 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 22 -substituted or unsubstituted heteroalkyl (e.g.
  • R 22 -substituted or unsubstituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 22 -substituted or unsubstituted heterocycloalkyl (e.g.
  • R 22 is R 22 -substituted alkyl (e.g. C 6 -Cio aryl or C 6 aryl), or R 22 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 6 is R 22 -substituted alkyl (e.g.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 22 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 22 -substituted cycloalkyl (e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl), R 22 -substituted heterocycloalkyl (e.g.
  • R 22 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl), unsubstituted heteroalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Ci 0 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 23 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 23 -substituted or unsubstituted cycloalkyl (e.g.
  • X 22 is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 24 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 24 -substituted or unsubstituted cycloalkyl (e.g.
  • X 23 is a halogen.
  • L 1 is a bond. In embodiments, L 1 is a substituted or unsubstituted Ci- C 8 alkylene. In embodiments, L 1 is a substituted or unsubstituted Ci-C 6 alkylene. In
  • L 1 is a substituted or unsubstituted C 1 -C4 alkylene. In embodiments, L 1 is a substituted or unsubstituted Ci-C 3 alkylene. In embodiments, L 1 is a substituted or unsubstituted Ci-C 2 alkylene. In embodiments, L 1 is a substituted or unsubstituted methylene. In embodiments, L 1 is a substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted 4 to 8 membered heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 1 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 1 is a substituted
  • L 1 is R 25 -substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, C 1 -C 4 alkylene, Ci-C 3 alkylene, Ci-C 2 alkylene, or methylene) or R 25 -substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene).
  • alkylene e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, C 1 -C 4 alkylene, Ci-C 3 alkylene, Ci-C 2 alkylene, or methylene
  • R 25 -substituted or unsubstituted heteroalkylene e.g. 2 to 10 membere
  • L 1 is unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, C 1 -C 4 alkylene, Ci-C 3 alkylene, Ci-C 2 alkylene, or methylene) or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene).
  • L 1 is R 25 -substituted alkylene (e.g.
  • L 1 is an unsubstituted alkylene (e.g.
  • Ci-C 8 alkylene Ci-C 6 alkylene, C 1 -C4 alkylene, C 1 -C3 alkylene, C 1 -C 2 alkylene, or methylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene).
  • unsubstituted heteroalkylene e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 26 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 26 -substituted or unsubstituted cycloalkyl (e.g.
  • R 26 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 26 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 26 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 25 is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl R 27 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 27 -substituted or unsubstituted cycloalkyl (e.g.
  • R 27 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 27 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 27 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 26 is a halogen.
  • L 2 is unsubstituted Ci-C 8 alkylene. In embodiments, L 2 is
  • L 2 is an unsubstituted Ci-C 2 alkylene. In embodiments, L 2 is an unsubstituted C 2 alkylene. In embodiments, L 2 is an unsubstituted methylene.
  • L 3 is a bond, substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
  • L 3 is a bond.
  • L 3 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • L 3 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), or substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 3 is a substituted or unsubstituted Ci-C 8 alkylene, or substituted or
  • L 3 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or Ci-C 4 alkylene). In embodiments, L 3 is a substituted or unsubstituted Ci-C 8 alkylene. In embodiments, L 3 is a substituted or unsubstituted Ci-C 6 alkylene. In embodiments, L 3 is a substituted or unsubstituted Ci-C 4 alkylene. In embodiments, L 3 is a substituted or unsubstituted C 1 -C 5 alkylene. In embodiments, L 3 is a substituted or unsubstituted C 5 alkylene.
  • alkylene e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or Ci-C 4 alkylene.
  • L 3 is a substituted C 1 -C 5 alkylene. In embodiments, L 3 is a substituted C 5 alkylene. In embodiments, L 3 is an unsubstituted C 1 -C5 alkylene. In embodiments, L 3 is an unsubstituted C 5 alkylene. In embodiments, L 3 is a substituted or unsubstituted Ci-C 4 alkylene. In
  • L 3 is a substituted or unsubstituted C 4 alkylene. In embodiments, L 3 is a substituted Ci-C 4 alkylene. In embodiments, L 3 is a substituted C 4 alkylene. In embodiments, L 3 is an unsubstituted Ci-C 4 alkylene. In embodiments, L 3 is an unsubstituted C 4 alkylene. In embodiments, L 3 is a substituted or unsubstituted Ci-C 3 alkylene. In embodiments, L 3 is a substituted or unsubstituted C 3 alkylene. In embodiments, L 3 is a substituted Ci-C 3 alkylene. In embodiments, L 3 is a substituted C 3 alkylene. In embodiments, L 3 is a substituted Ci-C 3 alkylene. In embodiments, L 3 is a substituted C 3 alkylene.
  • L 3 is an unsubstituted Ci-C 3 alkylene. In embodiments, L 3 is an unsubstituted C 3 alkylene. In embodiments, L 3 is a substituted or unsubstituted Ci-C 2 alkylene. In embodiments, L 3 is a substituted or unsubstituted C 2 alkylene. In embodiments, L 3 is a substituted C 1 -C 2 alkylene. In embodiments, L 3 is a substituted C 2 alkylene. In embodiments, L 3 is an unsubstituted C 1 -C 2 alkylene. In embodiments, L 3 is an unsubstituted C 2 alkylene.
  • L 3 is a substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 3 is a substituted or unsubstituted 2 to 10 membered heteroalkylene.
  • L 3 is a substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 3 is a substituted or unsubstituted 4 to 8 membered heteroalkylene.
  • L 3 is a substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 3 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted Ci-C 8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
  • L 3 is a substituted or unsubstituted - H-(Ci-C 8 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(Ci-C 6 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(Ci-C 5 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(Ci-C 4 alkylene) -.
  • L 3 is a substituted - H-(Ci-C 8 alkylene) -. In embodiments, L 3 is a substituted - H-(Ci-C7 alkylene) -. In embodiments, L 3 is a substituted - H-(Ci-C 6 alkylene) -. In embodiments, L 3 is a substituted - H-(Ci-C5 alkylene) -. In embodiments, L 3 is a substituted - H-(Ci-C 4 alkylene) -. In embodiments, L 3 is an
  • L 3 is an unsubstituted - H-(Ci-C 8 alkylene) -.
  • L 3 is an unsubstituted - H-(Ci-C 7 alkylene) -.
  • L 3 is an unsubstituted - H-(Ci-C 6 alkylene) -.
  • L 3 is an unsubstituted - H-(Ci-C5 alkylene) -.
  • L 3 is an unsubstituted - H- (Ci-C 4 alkylene) -.
  • L 3 is a substituted or unsubstituted - H-(C 8 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(C 7 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(C 6 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H-(C 5 alkylene) -. In embodiments, L 3 is a substituted or unsubstituted - H- (C 4 alkylene) -. In embodiments, L 3 is a substituted - H-(C 8 alkylene) -.
  • L 3 is a substituted - H-(C 7 alkylene) -. In embodiments, L 3 is a substituted - H-(C 6 alkylene) -. In embodiments, L 3 is a substituted - H-(C5 alkylene) -. In embodiments, L 3 is a substituted - H- (C 4 alkylene) -. In embodiments, L 3 is an unsubstituted - H-(C 8 alkylene) -. In embodiments, L 3 is an unsubstituted - H-(C 7 alkylene) -. In embodiments, L 3 is an unsubstituted - H-(C 6 alkylene) -. In embodiments, L 3 is an unsubstituted - H-(C5 alkylene) -. In embodiments, L 3 is an unsubstituted - H-(C 4 alkylene) -.
  • L 3 is a substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L 3 is a substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L 3 is a substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L 3 is a substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L 3 is a substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L 3 is a substituted 5 membered heteroalkylene. In embodiments, L 3 is a substituted 6 membered heteroalkylene.
  • L 3 is a substituted 7 membered heteroalkylene. In embodiments, L 3 is a substituted 8 membered heteroalkylene. In embodiments, L 3 is a substituted 9 membered heteroalkylene. In embodiments, L 3 is an unsubstituted 5 membered heteroalkylene. In embodiments, L 3 is an unsubstituted 6 membered heteroalkylene. In embodiments, L 3 is an unsubstituted 7 membered heteroalkylene. In embodiments, L 3 is an unsubstituted 8 membered heteroalkylene. In embodiments, L 3 is an unsubstituted 9 membered heteroalkylene.
  • L 3 is an oxo-substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted or unsubstituted 9 membered heteroalkylene.
  • L 3 is an oxo-substituted 5 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted 6 membered heteroalkylene. In embodiments, L 3 is an oxo-substituted 7
  • L 3 is an oxo-substituted 8 membered
  • L 3 is an oxo-substituted 9 membered heteroalkylene. In embodiments, L 3 is - H- H-C(O)-. In embodiments, L 3 is - H-C(O)-. In embodiments, L 3 is - H-CH 2 -C(0)-.
  • L 3 is R 28 -substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), R 28 -substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R 28 -substituted or unsubstituted cycloalkylene (e.g. C 3 -C 8 cycloalkylene, C 4 -C 8 cycloalkylene, or C 5 -C 6
  • alkylene e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene
  • R 28 -substituted or unsubstituted heteroalkylene
  • R 28 -substituted or unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered
  • R 28 -substituted or unsubstituted arylene e.g. C 6 -Ci 0 arylene or C 6 arylene
  • R 28 -substituted or unsubstituted heteroarylene e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • L 3 is R 28 -substituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), R 28 -substituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R 28 -substituted cycloalkylene (e.g.
  • R 28 -substituted heterocycloalkylene e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene
  • R 28 -substituted arylene e.g. C 6 -Ci 0 arylene or C 6 arylene
  • R 28 - substituted heteroaryl ene e.g. 5 to 10 membered heteroaryl ene, 5 to 9 membered heteroaryl ene, or 5 to 6 membered heteroarylene).
  • L 3 is an unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g.
  • alkylene e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene
  • unsubstituted heteroalkylene e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene
  • heterocycloalkylene unsubstituted arylene (e.g. C 6 -Cio arylene or C 6 arylene), or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
  • arylene e.g. C 6 -Cio arylene or C 6 arylene
  • heteroarylene e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 29 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 29 -substituted or unsubstituted cycloalkyl (e.g.
  • R 29 is a 2 to 10 membered substituted or unsubstituted heteroalkyl.
  • R 28 is a 2 to 10 membered substituted or unsubstituted heteroalkyl.
  • R 28 is a 10 membered substituted or unsubstituted heteroalkyl. In embodiments, R 28 is a substituted or unsubstituted 9 membered heteroalkyl. In embodiments, R 28 is a substituted or unsubstituted 8 membered heteroalkyl. In embodiments, R 28 is a substituted or unsubstituted 7 membered heteroalkyl. In embodiments, R 28 is a substituted or unsubstituted 6 membered heteroalkyl. In embodiments, R 28 is a substituted or unsubstituted 5 membered heteroalkyl. X 28 is a halogen.
  • R 28 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 28 is a substituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 28 is an unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 28 is a substituted or unsubstituted Ci-C 8 alkylene. In embodiments, R 28 is a substituted or unsubstituted Ci-C 6 alkylene. In embodiments, R 28 is a substituted or unsubstituted C 1 -C 4 alkylene. In
  • R 28 is a substituted or unsubstituted Ci-C 2 alkylene. In embodiments, R 28 is a substituted or unsubstituted C 2 -C 4 alkylene. In embodiments, R 28 is a substituted or
  • R 28 is a substituted Ci-C 8 alkylene.
  • R 28 is a substituted Ci-C 6 alkylene. In embodiments, R 28 is a substituted C 1 -C 4 alkylene. In embodiments, R 28 is a substituted Ci-C 2 alkylene. In embodiments, R 28 is a substituted C 2 -C 4 alkylene. In embodiments, R 28 is a substituted C 4 alkylene. In embodiments, R 28 is an unsubstituted Ci-C 8 alkylene. In embodiments, R 28 is an unsubstituted Ci-C 6 alkylene. In embodiments, R 28 is an unsubstituted C 1 -C 4 alkylene. In embodiments, R 28 is an unsubstituted Ci-C 2 alkylene. In embodiments, R 28 is an unsubstituted C 2 -C 4 alkylene. In embodiments, R 28 is an unsubstituted C 4 alkylene.
  • R 28 is a substituted Ci-C 8 alkylene substituted with a detectable moiety. In embodiments, R 28 is a substituted Ci-C 6 alkylene substituted with a detectable moiety. In embodiments, R 28 is a substituted C 1 -C 4 alkylene substituted with a detectable moiety. In embodiments, R 28 is a substituted Ci-C 2 alkylene substituted with a detectable moiety. In embodiments, R 28 is a substituted C 2 -C 4 alkylene substituted with a detectable moiety. In embodiments, R 28 is a substituted C 4 alkylene substituted with a detectable moiety.
  • R 28 is a substituted Ci-C 8 alkylene substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted Ci-C 6 alkylene substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted C 1 -C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted Ci-C 2 alkylene substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted C 2 -C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the fluorescein
  • R is a substituted Ci-C 8 alkylene substituted with a thiourea- detectable moiety.
  • R 28 is a substituted Ci-C 6 alkylene substituted with a thiourea-detectable moiety.
  • R 28 is a substituted C 1 -C 4 alkylene substituted with a thiourea-detectable moiety.
  • R 28 is a substituted C 1 -C 2 alkylene substituted with a thiourea-detectable moiety.
  • R 28 is a substituted C 2 -C 4 alkylene substituted with a thiourea-detectable moiety.
  • R 28 is a substituted C 4 alkylene substituted with a thiourea-detectable moiety.
  • R 28 is a substituted Ci-C 8 alkylene substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted Ci-C 6 alkylene substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted C 1 -C4 alkylene substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted Ci-C 2 alkylene substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted C 2 -C 4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted C 4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
  • R is a substituted 2 to 10 membered heteroalkyl.
  • R 28 is a substituted 10 membered heteroalkyl.
  • R 28 is a substituted 9 membered heteroalkyl.
  • R 28 is a substituted 8 membered heteroalkyl.
  • R 2 is a substituted 7 membered heteroalkyl.
  • R 28 is a substituted 6 membered heteroalkyl.
  • R 28 is a substituted 5 membered heteroalkyl.
  • R 28 is a substituted 2 to 10 membered heteroalkyl substituted with a detectable moiety.
  • R 28 is a substituted 2 to 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 2 to 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 2 to 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 9 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 8 membered heteroalkyl substituted with a detectable moiety.
  • R 28 is a substituted 7 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 5 membered heteroalkyl substituted with a detectable moiety.
  • R 28 is a substituted 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 3 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 28 is a substituted 2 membered heteroalkyl substituted with a detectable moiety.
  • R 28 is a substituted 2 to 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 2 to 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 2 to 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 2 to 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 9 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 7 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety.
  • R 28 is a substituted 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 5 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 3 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 28 is a substituted 2 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the flu
  • R is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 28 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 28 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 28 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 28 is a substituted 10 membered heteroalkyl substituted with a thiourea- detectable moiety.
  • R 28 is a substituted 9 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 7 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 5 membered heteroalkyl substituted with a thiourea-detectable moiety. In
  • R 28 is a substituted 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 3 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 28 is a substituted 2 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 28 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 9 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 7 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety.
  • R 28 is a substituted 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 5 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 3 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 28 is a substituted 2 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
  • R is a substituted 2 to 10 membered heteroalkyl.
  • R 28 is a substituted 10 membered heteroalkyl.
  • R 28 is a substituted 9 membered heteroalkyl.
  • R 28 is a substituted 8 membered heteroalkyl.
  • R 28 is a substituted 7 membered heteroalkyl.
  • R 28 is a substituted 6 membered heteroalkyl.
  • R 28 is a substituted 5 membered heteroalkyl.
  • R 30 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 30 -substituted or unsubstituted cycloalkyl e.g.
  • X 29 is a halogen.
  • L 3 is N(R 7 )-.
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • X 7 is halogen.
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 .
  • R 7 is hydrogen.
  • R 7 is R 34 -substituted or unsubstituted alkyl (e.g.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 34 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 34 -substituted or unsubstituted cycloalkyl (e.g.
  • R 34 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl R 34 -substituted or unsubstituted aryl (e.g. C 6 -Ci 0 aryl or C 6 aryl), or R 34 - substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 7 is a halogen.
  • R 7 is R 34 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), R 34 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 34 -substituted cycloalkyl (e.g.
  • R 34 -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 34 -substituted aryl e.g. C 6 - C 10 aryl or C 6 aryl
  • R 34 -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 7 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Cio aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 35 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 35 -substituted or unsubstituted cycloalkyl (e.g.
  • X 34 is a halogen.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 36 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 36 -substituted or unsubstituted cycloalkyl (e.g.
  • R 36 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 36 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 36 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 35 is a halogen.
  • L 4 is a substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene.
  • L 4 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • L 4 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C 4 alkylene), or substituted or unsubstituted
  • heteroalkylene e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted Ci-C 8 alkylene, or substituted or
  • L 4 is an oxo- substituted Ci-C 8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, L 4 is a substituted or unsubstituted Ci-C 8 alkylene. In embodiments, L 4 is a substituted or unsubstituted Ci-C 6 alkylene. In embodiments, L 4 is a substituted or unsubstituted C 1 -C4 alkylene. In embodiments, L 4 is a substituted or unsubstituted C 1 -C 5 alkylene. In embodiments, L 4 is a substituted or unsubstituted C 5 alkylene.
  • alkylene e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or C 1 -C 4 alkylene. In embodiments, L 4 is a substituted or unsubstituted Ci-C 8 alkylene. In embodiments, L 4 is a substitute
  • L 4 is a substituted C 1 -C5 alkylene. In embodiments, L 4 is a substituted C 5 alkylene. In embodiments, L 4 is an unsubstituted C 1 -C5 alkylene. In embodiments, L 4 is an unsubstituted C 5 alkylene.
  • L 4 is a substituted or unsubstituted - H-(Ci-C 8 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(Ci-C 6 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(Ci-C 5 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(Ci-C 4 alkylene) -.
  • L 4 is a substituted - H-(Ci-C 8 alkylene) -. In embodiments, L 4 is a substituted - H-(Ci-C7 alkylene) -. In embodiments, L 4 is a substituted - H-(Ci-C 6 alkylene) -. In embodiments, L 4 is a substituted - H-(Ci-C5 alkylene) -. In embodiments, L 4 is a substituted - H-(Ci-C 4 alkylene) -. In embodiments, L 4 is an
  • L 4 is an unsubstituted - H-(Ci-C 8 alkylene) -.
  • L 4 is an unsubstituted - H-(Ci-C 7 alkylene) -.
  • L 4 is an unsubstituted - H-(Ci-C 6 alkylene) -.
  • L 4 is an unsubstituted - H-(Ci-C5 alkylene) -.
  • L 4 is an unsubstituted - H- (C 1 -C4 alkylene) -.
  • L 4 is a substituted or unsubstituted - H-(C 8 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(C 7 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(C 6 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H-(C 5 alkylene) -. In embodiments, L 4 is a substituted or unsubstituted - H- (C 4 alkylene) -. In embodiments, L 4 is a substituted - H-(C 8 alkylene) -.
  • L 4 is a substituted - H-(C 7 alkylene) -. In embodiments, L 4 is a substituted - H-(C 6 alkylene) -. In embodiments, L 4 is a substituted - H-(C5 alkylene) -. In embodiments, L 4 is a substituted - H- (C 4 alkylene) -. In embodiments, L 4 is an unsubstituted - H-(C 8 alkylene) -. In embodiments, L 4 is an unsubstituted - H-(C 7 alkylene) -. In embodiments, L 4 is an unsubstituted - H-(C 6 alkylene) -. In embodiments, L 4 is an unsubstituted - H-(C 5 alkylene) -. In embodiments, L 4 is an unsubstituted - H-(C 4 alkylene) -.
  • L 4 is a substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L 4 is a substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L 4 is a substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L 4 is a substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L 4 is a substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L 4 is a substituted 5 membered heteroalkylene. In embodiments, L 4 is a substituted 6 membered heteroalkylene.
  • L 4 is a substituted 7 membered heteroalkylene. In embodiments, L 4 is a substituted 8 membered heteroalkylene. In embodiments, L 4 is a substituted 9 membered heteroalkylene. In embodiments, L 4 is an unsubstituted 5 membered heteroalkylene. In embodiments, L 4 is an unsubstituted 6 membered heteroalkylene. In embodiments, L 4 is an unsubstituted 7 membered heteroalkylene. In embodiments, L 4 is an unsubstituted 8 membered heteroalkylene. In embodiments, L 4 is an unsubstituted 9 membered heteroalkylene.
  • L 4 is an oxo-substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted or unsubstituted 9 membered heteroalkylene.
  • L 4 is an oxo-substituted 5 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted 6 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted 7 membered heteroalkylene. In embodiments, L 4 is an oxo-substituted 8 membered
  • L 4 is an oxo-substituted 9 membered heteroalkylene. In embodiments, L 4 is - H- H-C(O)-. In embodiments, L 4 is - H-C(O)-. In embodiments, L 4 is - - H-CH 2 -C(0)-.
  • L 4 is a substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene).
  • L 4 is a substituted or unsubstituted 2 to 10 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted 4 to 8 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted 2 to 6 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted 2 to 4 membered heteroalkylene.
  • L 4 is a substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L 4 is a substituted or unsubstituted arylene. In embodiments, L 4 is a substituted or unsubstituted heteroarylene. In embodiments, L 4 is a substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L 4 is a substituted or unsubstituted phenylene. In embodiments, L 4 is a substituted or unsubstituted 5 to 6 membered heteroarylene.
  • L 4 is an unsubstituted phenylene.
  • L 4 may be a substituted or unsubstituted 4 to 6 membered heterocycloalkylene.
  • L 4 may be a substituted or unsubstituted 5 or 6 membered heterocycloalkylene.
  • L 4 may be substituted or unsubstituted 5 membered heterocycloalkylene.
  • L 4 may be a substituted or unsubstituted heterocycloalkylene such as substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted imidazolidinylene, substituted or unsubstituted oxazolidinylene, substituted or unsubstituted thiazolidinylene, substituted or unsubstituted dioxolanylene, substituted or unsubstituted dithiolanylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted dioxanylene, substituted or unsubstituted dithianylene, substituted or unsubstituted aziridinylene, substituted or
  • L 4 may be a substituted or unsubstituted 6 membered heterocycloalkylene.
  • L 4 may be an unsubstituted 6 membered heterocycloalkylene.
  • L 4 may be an unsubstituted 5 membered heterocycloalkylene.
  • L 4 may be substituted or unsubstituted C 3 -C 8 cycloalkylene.
  • L 4 may be substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • L 4 may be unsubstituted C 3 -C 8
  • L 4 may be unsubstituted 3 to 8 membered heterocycloalkylene.
  • L 4 may be substituted or unsubstituted heteroarylene.
  • L 4 may be substituted or unsubstituted 5 or 6 membered heteroarylene.
  • L 4 may be a substituted or unsubstituted heteroarylene such as, for example, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted furanylene, substituted or unsubstituted thiophenylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted pyranylene, substituted or unsubstituted thiopyranylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted pyrimindylene, substituted or
  • L 4 may be substituted or unsubstituted pyridinylene.
  • L 4 may be substituted cycloalkylene.
  • L 4 may be unsubstituted cycloalkylene.
  • L 4 may be substituted heterocycloalkylene.
  • L 4 may be unsubstituted
  • L 4 may be substituted C 3 -C 8 cycloalkylene.
  • L 4 may be unsubstituted C 3 -C 8 cycloalkylene.
  • L 4 may be substituted 3 to 8 membered heterocycloalkylene.
  • L 4 may be unsubstituted 3 to 8 membered heterocycloalkylene.
  • L 4 is an unsubstituted 5 to 6 membered heteroarylene.
  • L 4 is R 31 -substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), R 31 - substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R 31 -substituted or unsubstituted cycloalkylene (e.g. C 3 -C 8 cycloalkylene, C 4 -C 8 cycloalkylene, or C5-C6
  • alkylene e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene
  • R 31 - substituted or unsubstituted heteroalkylene e.g. 2 to 10
  • R 31 -substituted or unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered
  • heterocycloalkylene R 31 - substituted or unsubstituted arylene (e.g. C 6 -Ci 0 arylene or C 6 arylene), or R 31 - substituted or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
  • arylene e.g. C 6 -Ci 0 arylene or C 6 arylene
  • heteroarylene e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • L 4 is R 31 -substituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), R 31 -substituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R 31 -substituted cycloalkylene (e.g.
  • R 31 - substituted heterocycloalkylene e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene
  • R 31 - substituted arylene e.g. C 6 -Cio arylene or C 6 arylene
  • R 31 - substituted heteroarylene e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene.
  • L 4 is an unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g.
  • alkylene e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C4 alkylene
  • unsubstituted heteroalkylene e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene
  • R 31 is independently halogen, -CX 31 3 , -CN, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -
  • R 32 e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 32 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 32 -substituted or unsubstituted cycloalkyl e.g.
  • R 32 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 32 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 32 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 31 is a halogen.
  • R 31 is a substituted or unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci- C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 31 is a substituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 31 is an unsubstituted alkylene (e.g. Ci-C 8 alkylene, Ci-C 6 alkylene, or C 1 -C 4 alkylene). In embodiments, R 31 is a substituted or unsubstituted Ci-C 8 alkylene. In embodiments, R 31 is a substituted or unsubstituted Ci-C 6 alkylene. In embodiments, R 31 is a substituted or unsubstituted C 1 -C 4 alkylene. In
  • R 31 is a substituted or unsubstituted Ci-C 2 alkylene. In embodiments, R 31 is a substituted or unsubstituted C 2 -C 4 alkylene. In embodiments, R 31 is a substituted or
  • R 31 is a substituted Ci-C 8 alkylene.
  • R 31 is a substituted Ci-C 6 alkylene. In embodiments, R 31 is a substituted C 1 -C 4 alkylene. In embodiments, R 31 is a substituted Ci-C 2 alkylene. In embodiments, R 31 is a substituted C 2 -C 4 alkylene. In embodiments, R 31 is a substituted C 4 alkylene. In embodiments, R 31 is an unsubstituted Ci-C 8 alkylene. In embodiments, R 31 is an unsubstituted Ci-C 6 alkylene. In embodiments, R 31 is an unsubstituted C 1 -C 4 alkylene. In embodiments, R 31 is an unsubstituted C 1 -C 2 alkylene. In embodiments, R 31 is an unsubstituted C 2 -C4 alkylene. In embodiments, R 31 is an unsubstituted C 4 alkylene.
  • R 31 is a substituted Ci-C 8 alkylene substituted with a detectable moiety. In embodiments, R 31 is a substituted Ci-C 6 alkylene substituted with a detectable moiety. In embodiments, R 31 is a substituted C 1 -C 4 alkylene substituted with a detectable moiety. In embodiments, R 31 is a substituted Ci-C 2 alkylene substituted with a detectable moiety. In embodiments, R 31 is a substituted C 2 -C 4 alkylene substituted with a detectable moiety. In embodiments, R 31 is a substituted C 4 alkylene substituted with a detectable moiety.
  • R 31 is a substituted Ci-C 8 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted Ci-C 6 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted C 1 -C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted Ci-C 2 alkylene substituted with a fluorescein isothiocyanate detectable moiety.
  • R 31 is a substituted C 2 -C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted C 4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein
  • R 31 is a substituted Ci-C 8 alkylene substituted with a thiourea- detectable moiety.
  • R 31 is a substituted Ci-C 6 alkylene substituted with a thiourea-detectable moiety.
  • R 31 is a substituted C 1 -C 4 alkylene substituted with a thiourea-detectable moiety.
  • R 31 is a substituted Ci-C 2 alkylene substituted with a thiourea-detectable moiety.
  • R 31 is a substituted C 2 -C 4 alkylene substituted with a thiourea-detectable moiety.
  • R 31 is a substituted C 4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted Ci-C 8 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted Ci-C 6 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted C 1 -C 4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted C 1 -C 2 alkylene substituted with a thiourea-fluorescein detectable moiety.
  • R 31 is a substituted C 2 -C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted C 4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
  • R 31 is a substituted 2 to 10 membered heteroalkyl. In embodiments, R 31 is a substituted 10 membered heteroalkyl. In embodiments, R 31 is a substituted 9 membered heteroalkyl. In embodiments, R 31 is a substituted 8 membered heteroalkyl. In embodiments, R 31 is a substituted 7 membered heteroalkyl. In embodiments, R 31 is a substituted 6 membered heteroalkyl. In embodiments, R 31 is a substituted 5 membered heteroalkyl.
  • R 31 is a substituted 2 to 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 2 to 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 2 to 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 2 to 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 9 membered heteroalkyl substituted with a detectable moiety.
  • R 31 is a substituted 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 7 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 5 membered heteroalkyl substituted with a detectable moiety.
  • R 31 is a substituted 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 3 membered heteroalkyl substituted with a detectable moiety. In embodiments, R 31 is a substituted 2 membered heteroalkyl substituted with a detectable moiety.
  • R 31 is a substituted 2 to 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 2 to 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 2 to 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 2 to 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety.
  • R 31 is a substituted 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 9 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 7 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety.
  • R 31 is a substituted 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 5 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 3 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R 31 is a substituted 2 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the
  • fluorescein isothiocyanate detectable moiety is bodiments
  • R 31 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 10 membered heteroalkyl substituted with a thiourea- detectable moiety.
  • R 31 is a substituted 9 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 7 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 5 membered heteroalkyl substituted with a thiourea-detectable moiety. In
  • R 31 is a substituted 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 3 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R 31 is a substituted 2 membered heteroalkyl substituted with a thiourea-detectable moiety.
  • R 31 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety.
  • R 31 is a substituted 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 9 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 7 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety.
  • R 31 is a substituted 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 5 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 3 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R 31 is a substituted 2 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
  • R 31 is R 32 -substituted or unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl). In embodiments, R 31 is R 32 -substituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl). In embodiments, R 31 is an unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl).
  • R 31 is R 32 -substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 31 is R 32 -substituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 31 is an unsubstituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 31 is R 32 -substituted or unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R 31 is R 32 -substituted or unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R 31 is R 32 -substituted or unsubstituted 6 to 9 membered
  • R 31 is R 32 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8
  • R 31 is R 32 -substituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 31 is an unsubstituted cycloalkyl (e.g., C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C6 cycloalkyl).
  • R 31 is R 32 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 31 is R 32 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 31 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 31 is R 32 -substituted or unsubstituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 31 is R 32 -substituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 31 is an unsubstituted aryl (e.g., C 6 -Ci 0 aryl, C 10 aryl, or phenyl).
  • R 31 is R 32 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 31 is R 32 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 31 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R 31 is a substituted 2 to 10 membered heteroalkyl. In embodiments, R 31 is a substituted 10 membered heteroalkyl. In embodiments, R 31 is a substituted 9 membered heteroalkyl. In embodiments, R 31 is a substituted 8 membered heteroalkyl. In embodiments, R 31 is a substituted 7 membered heteroalkyl. In embodiments, R 31 is a substituted 6 membered heteroalkyl. In embodiments, R 31 is a substituted 5 membered heteroalkyl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 33 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 33 -substituted or unsubstituted cycloalkyl (e.g.
  • R 33 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 33 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 33 -substituted or unsubstituted heteroaryl e.g.
  • R 32 is R 33 -substituted or unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 32 is R 33 -substituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl). In embodiments, R 32 is an unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl).
  • R 32 is R 33 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 32 is R 33 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R 32 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 32 is R 33 -substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 32 is an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 32 is R 33 -substituted 2 to 6 membered heteroalkyl.
  • R 32 is R 33 -substituted or unsubstituted cycloalkyl (e.g., C 3 -Ci 0 cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 32 is R 33 -substituted cycloalkyl (e.g., C 3 -Cio cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl).
  • R 32 is an unsubstituted cycloalkyl (e.g., C 3 -Cio cycloalkyl, C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkyl). In embodiments, R 32 is an unsubstituted C 3 -Cio cycloalkyl. In embodiments, R 32 is substituted or unsubstituted adamantanyl. [0234] In embodiments, R 32 is R 33 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 32 is R 33 -substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 32 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 32 is R 33 -substituted or unsubstituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 32 is R 33 -substituted aryl (e.g., C 6 -Ci 0 aryl, C 10 aryl, or phenyl). In embodiments, R 32 is an unsubstituted aryl (e.g., C 6 -Ci 0 aryl, C 10 aryl, or phenyl).
  • R 32 is R 33 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 32 is R 33 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 32 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • R is an unsubstituted alkyl (e.g., Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl).
  • R 33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl).
  • R 33 is an unsubstituted cycloalkyl (e.g., C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkyl, or C5-C 6 cycloalkyl).
  • R 33 is an unsubstituted C 3 -C 10 cycloalkyl. In embodiments, R 33 is substituted or unsubstituted adamantanyl. In embodiments, R 33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
  • R 33 is an unsubstituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 33 is R 33 -substituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 33 is an unsubstituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In embodiments, R 33 is an unsubstituted aryl (e.g., C 6 -Cio aryl, C 10 aryl, or phenyl). In
  • R 33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R 33 is independently oxo or H 2 .
  • L 4 is -N(R 8 )-
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 .
  • R 8 is hydrogen.
  • R 8 is R 37 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl), R 37 - substituted or unsubstituted heteroalkyl (e.g.
  • R 37 -substituted or unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C5-C6 cycloalkyl
  • R 37 -substituted or unsubstituted heterocycloalkyl e.g.
  • R 37 - substituted or unsubstituted aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • R 37 -substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • X 8 is a halogen.
  • R 8 is R 37 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), R 37 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 37 -substituted cycloalkyl (e.g.
  • R 37 -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 37 -substituted aryl e.g. C 6 - C 10 aryl or C 6 aryl
  • R 37 -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 8 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Cio aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 38 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 38 -substituted or unsubstituted cycloalkyl e.g.
  • X 37 is a halogen.
  • R 39 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 39 -substituted or unsubstituted cycloalkyl e.g.
  • X 38 is a halogen.
  • R 5 is hydrogen
  • R 9 is R 40 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci- C 4 alkyl), R 40 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 40 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci- C 4 alkyl
  • R 40 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl,
  • R 40 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • R 40 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 40 - substituted or unsubstituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 9 is R 40 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl), R 40 -substituted heteroalkyl (e.g.
  • R 40 -substituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkyl, or C 5 -C 6 cycloalkyl
  • R 40 -substituted heterocycloalkyl e.g.
  • R 40 -substituted aryl e.g. C 6 - Cio aryl or C 6 aryl
  • R 40 -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl
  • R 9 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or Ci-C 4 alkyl), unsubstituted heteroalkyl (e.g.
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Cio aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl R 41 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 41 - substituted or unsubstituted cycloalkyl (e.g.
  • X 40 is a halogen.
  • R 42 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 42 -substituted or unsubstituted cycloalkyl e.g.
  • R 42 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R 42 -substituted or unsubstituted aryl (e.g. C 6 -Cio aryl or C 6 aryl), or R 42 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • X 41 is a halogen.
  • R 10 is R 43 -substituted or unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 43 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 43 -substituted or unsubstituted cycloalkyl (e.g.
  • alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl
  • R 43 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered hetero
  • R 43 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 43 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 43 -substituted or unsubstituted heteroaryl e.g.
  • R 10 is R 43 -substituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), R 43 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 43 -substituted cycloalkyl (e.g.
  • R 43 -substituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 43 -substituted aryl e.g. C 6 - C 10 aryl or C 6 aryl
  • R 43 -substituted heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • R 10 is an unsubstituted alkyl (e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C 1 -C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g.
  • R 43 is independently halogen, -CX 43 3 , -CN, -OH, - H 2 , -COOH, -CO H 2 , -N0 2 , -SH, -
  • R 44 -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R 44 -substituted or unsubstituted cycloalkyl (e.g.
  • X 43 is a halogen.
  • R 45 -substituted or unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • R 45 -substituted or unsubstituted cycloalkyl e.g.
  • R 45 -substituted or unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl
  • R 45 -substituted or unsubstituted aryl e.g. C 6 -Cio aryl or C 6 aryl
  • R 45 -substituted or unsubstituted heteroaryl e.g.
  • X 44 is a halogen.
  • R 13 , R 13A , R 13B , R 13C , R 13D , R 16 , R 16A , R 16B , R 16C , R 16D , R 17 , R 18 , R 21 , R 24 , R 27 , R 30 , R 33 , R 36 , R 39 , R 42 , and R 45 are independently halogen, -CX 3 , -CN, -OH, -NH 2 , -COOH,
  • unsubstituted alkyl e.g. Ci-C 8 alkyl, Ci-C 6 alkyl, or C1-C4 alkyl
  • unsubstituted heteroalkyl e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl
  • unsubstituted cycloalkyl e.g. C 3 -C 8 cycloalkyl, C4-C 8 cycloalkyl, or C5-C6 cycloalkyl
  • unsubstituted heterocycloalkyl e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
  • heterocycloalkyl unsubstituted aryl (e.g. C 6 -Ci 0 aryl or C 6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
  • aryl e.g. C 6 -Ci 0 aryl or C 6 aryl
  • heteroaryl e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl.
  • X 26 , X 28 , X 29 , X 31 , X 32 , X 34 , X 35 , X 37 , X 38 , X 40 , X 41 , X 43 , and X 44 are independently -F, -CI, -Br, or -I.
  • X is -F.
  • X is -CI.
  • X is -Br.
  • X is -I.
  • X 1 is -F.
  • X 1 is -CI.
  • X 1 is -Br.
  • X 1 is -I.
  • X 2 is -F.
  • X 2 is -CI. In embodiments, X 2 is -Br. In embodiments, X 2 is -I. In embodiments, X 4 is -F. In embodiments, X 4 is -CI. In embodiments, X 4 is -Br. In embodiments, X 4 is -I. In embodiments, X 7 is -F. In embodiments, X 7 is -CI. In embodiments, X 7 is -Br. In embodiments, X 7 is -I. In embodiments, X 8 is -F. In embodiments, X 8 is -CI. In embodiments, X 8 is -Br. In embodiments, X 8 is -I.
  • X 9 is -F. In embodiments, X 9 is -CI. In embodiments, X 9 is -Br. In embodiments, X 9 is -I. In embodiments, X 10 is -F. In embodiments, X 10 is -CI. In embodiments, X 10 is -Br. In embodiments, X 10 is -I. In embodiments, X 11 is -F. In embodiments, X 11 is -CI. In
  • X 11 is -Br. In embodiments, X 11 is -I. In embodiments, X 12 is -F. In
  • X 12 is -CI. In embodiments, X 12 is -Br. In embodiments, X 12 is -I. In
  • X 14 is -F. In embodiments, X 14 is -CI. In embodiments, X 14 is -Br. In
  • X 14 is -I.
  • X 15 is -F.
  • X 15 is -CI.
  • X 15 is -Br. In embodiments, X 15 is -I.
  • X 19 is -F. In embodiments, X 19 is -CI. In embodiments, X 19 is -Br. In embodiments, X 19 is -I. In embodiments, X 20 is -F. In embodiments, X 20 is -CI. In
  • X is -Br. In embodiments, X is -I. In embodiments, X is -F. In
  • X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In
  • X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
  • X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
  • X 25 is -Br. In embodiments, X 25 is -I. In embodiments, X 26 is -F. In
  • X 26 is -CI. In embodiments, X 26 is -Br. In embodiments, X 26 is -I. In
  • X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
  • X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
  • X is -Br. In embodiments, X is -I. In embodiments, X is -F. In
  • X 31 is -CI. In embodiments, X 31 is -Br. In embodiments, X 31 is -I. In
  • X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
  • X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
  • X 34 is -Br. In embodiments, X 34 is -I. In embodiments, X 35 is -F. In
  • X 35 is -CI. In embodiments, X 35 is -Br. In embodiments, X 35 is -I. In
  • X 37 is -F. In embodiments, X 37 is -CI. In embodiments, X 37 is -Br. In
  • X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
  • X is -Br. In embodiments, X is -I. In embodiments, X is -F. In 40 ⁇
  • X is -CI.
  • X 4U is -Br.
  • ⁇ 4 ⁇ 0 is -I.
  • X 41 is -F. In embodiments, X 41 I i ⁇ s -CI. In embodiments, X 41 is -Br. In
  • X 41 is -I. In embodiments, X 4j is -F. In embodiments, X 43 is -CI. In
  • X 43 is -Br. In embodiments, X 4j is -I. In embodiments, X 44 is -F. In
  • X is -CI. In embodiments, X 44 is -Br. In embodiments, X 44 is -I
  • X 11A is -F.
  • X iiA is -CI.
  • X iiA is -Br
  • X 1 is -I.
  • X is -F.
  • X s -Br In embodiments, X is -I. In embodiments, X i 1 4 4 A A i ⁇ s -F. In
  • X s -CI In embodiments, X is -Br. In embodiments, X i 1 4 4 A A i ⁇ s -I. In embodiments, -F. In embodiments, X i3A is -CI. In embodiments, X i3A is -Br. In
  • X -I In embodiments, X 11B is -F. In embodiments, X 11B is -CI. In
  • X -Br In embodiments, X 11B is -I. In embodiments, X 12B is -F. In
  • X -CI In embodiments, X 12B is -Br. In embodiments, X 12B is -I. In
  • X -F In embodiments, X 14B is -CI. In embodiments, X 14B is -Br. In
  • X -I In embodiments, X 15B is -F. In embodiments, X 15B is -CI. In
  • X -Br In embodiments, X l3B is -I. In embodiments, X 11C is -F. In
  • X -CI In embodiments, X 11C is -Br. In embodiments, X 11C is -I. In embodiments, X 12C
  • X 12C is -CI. In embodiments, X 12C is -Br. In embodiments, X 12C
  • X 14C is -F. In embodiments, X 14C is -CI. In embodiments, X rl4C
  • X 14C is -I.
  • X 15C is -F.
  • X l3C is -Br.
  • X 15C is -I.
  • X -F In embodiments, X 11D is -CI. In embodiments, X 11D is -Br. In
  • X -I In embodiments, X 12D is -F. In embodiments, X 12D is -CI. In
  • X s -Br In embodiments, X is -I. In embodiments, X 1 1 4 4 L D I i ⁇ s -F. In
  • X s -CI In embodiments, X is -Br. In embodiments, X i 1 4 4 U D i ⁇ s -I. In
  • X s -F In embodiments, X is -CI. In embodiments, ⁇ 13 ⁇ is -Br. In
  • nl and n2 are independently an integer from 0 to 4. In embodiments, nl and n2 are independently an integer from 0 to 3. In embodiments, nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments, ml, m2, vl and v2 are independently 1 or 2. In embodiments, ml is 1 or 2. In embodiments, ml is 1. In embodiments, ml is 2.
  • m2 is 1 or 2. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, vl is 1 or 2. In embodiments, vl is 1. In embodiments, vl is 2. In embodiments, v2 is 1 or 2. In embodiments, v2 is 1. In embodiments, v2 is 2.
  • zl is an integer from 0 to 5. In embodiments, zl is an integer from 1 to 5. In embodiments, zl is an integer from 2 to 5. In embodiments, zl is an integer from 3 to 5. In embodiments, zl is 4 or 5. In embodiments, zl is an integer from 1 to 3. In embodiments, zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In
  • zl is 4. In embodiments, zl is 5. In embodiments, z2 is an integer from 0 to 9. In embodiments, z2 is an integer from 1 to 9. In embodiments, z2 is an integer from 2 to 9. In embodiments, z2 is an integer from 0 to 5. In embodiments, z2 is an integer from 1 to 5. In embodiments, z2 is an integer from 2 to 5. In embodiments, z2 is an integer from 3 to 5. In embodiments, z2 is 4 or 5. In embodiments, z2 is an integer from 1 to 3. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6. In embodiments, z2 is 7. In embodiments, z2 is 8. In embodiments, z2 is 9.
  • z3 is 1. In embodiments, where L 3 is substituted or unsubstituted arylene, z3 is 0. In embodiments, where L 3 is substituted or unsubstituted heteroarylene, z3 is 1. In embodiments, where L 3 is substituted or unsubstituted heteroarylene, z3 is 0.
  • the compound has the formula
  • R 6 are as described herein.
  • the compound has the formula
  • Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • Ring A may be substituted or unsubstituted cycloalkylene. Ring A may be substituted or unsubstituted C3-C8 cycloalkylene. Ring A may be substituted cycloalkylene. Ring A may be substituted C 3 -C 8 cycloalkylene. Ring A may be unsubstituted cycloalkylene. Ring A may be unsubstituted C 3 -C 8 cycloalkylene.
  • Ring A may be substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
  • Ring A may be a substituted or unsubstituted 4 to 6 membered heterocycloalkylene. Ring A may be a substituted or unsubstituted 5 or 6 membered heterocycloalkylene. Ring A may be substituted or unsubstituted 5 membered heterocycloalkylene. Ring A may be substituted or unsubstituted 6 membered heterocycloalkylene.
  • Ring A is a substituted or unsubstituted heterocycloalkylene (e.g., substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted imidazolidinylene, substituted or unsubstituted oxazolidinylene, substituted or unsubstituted thiazolidinylene, substituted or unsubstituted dioxolanylene, substituted or unsubstituted dithiolanylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted dioxanylene, substituted or unsubstituted dithianylene, substituted or unsubstituted aziridinylene, substituted or
  • Ring A is a substituted or unsubstituted C 6 -Ci2 arylene. In embodiments, Ring A is a substituted C 6 -Ci 2 arylene. In embodiments, Ring A is an
  • Ring A is a substituted or unsubstituted C 6 -Ci 0 arylene. In embodiments, Ring A is a substituted C 6 -Cio arylene. In embodiments, Ring A is an unsubstituted C 6 -Cio arylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is a substituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is a substituted naphthylene. In embodiments, Ring A is an unsubstituted biphenyl. In embodiments, Ring A is a substituted biphenyl.
  • Ring A is a substituted or unsubstituted 5 to 10 membered
  • Ring A is a substituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 5 membered heteroarylene. In embodiments, Ring A is a substituted 5 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 membered heteroarylene.
  • Ring A is a substituted or unsubstituted 6 membered heteroarylene. In embodiments, Ring A is a substituted 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted 6 membered heteroarylene.
  • Ring A may be unsubstituted triazolylene. Ring A may be substituted triazolylene. Ring A may be unsubstituted tetrazolylene. Ring A may be substituted tetrazolylene. In embodiments, Ring A is substituted or unsubstituted pyridylene. Ring A may be substituted or unsubstituted heteroarylene.
  • Ring A may be a substituted or unsubstituted heteroarylene such as, for example, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted furanylene, substituted or unsubstituted thiophenylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted pyranylene, substituted or unsubstituted thiopyranylene, substituted or unsubstituted
  • substituted or unsubstituted heteroarylene such as, for example, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted furanylene, substituted or unsubsti
  • pyrazinylene substituted or unsubstituted pyrimindylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted oxazinylene, substituted or unsubstituted
  • Ring A may be substituted or unsubstituted doxinylene, substituted or unsubstituted dithiinylene, substituted or unsubstituted azetylene, substituted or unsubstituted oxetylene, substituted or unsubstituted thietylene, substituted or unsubstituted azirinylene, substituted or unsubstituted oxirenylene or substituted or unsubstituted thienylene.
  • Ring A may be substituted or
  • the compound has the formula:
  • the compound has the formula:
  • R 2 , Z2, L 1 , L 3 , L 4 , and R 6 are as described herein.
  • the compound has the formula: L 3 — L 4 — NR 5 R 6
  • R 1 , R 1 2 , R 1 3 , R 1 4 , and R 1 5 are each independently a moiety of R 1 as described herein, including in embodiments.
  • a compound as described herein may include multiple instances of R 1 , R 2 , and/or other variables.
  • each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity.
  • R 1 and/or R 2 may be referred to, for example, as R 1 J , R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 2 R 2 2 , R 2 3 , R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 , R 2 9 , respectively, wherein the definition of R 1 is assumed by R u , R 1 2 , R 1 3 , R 1 4 , R 1 5 ; R 2 is assumed by R 2 ⁇ R 2 2 , R 2 3 , R 2 4 , R 2 5 , R 2 6 , R 2 7 , R 2 8 , R 2 9 .
  • the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, or table).
  • the compound has the formula:
  • R 2 , z2, L 1 , L 3 , and L 4 are as described herein.
  • the compound has the formula:
  • R 31 are as described herein and z31 is an integer from 0 to 4. In embodiments, z31 is 0 or 1. In embodiments, z31 is 0. In embodiments, z31 is 1. In embodiments, z31 is 2. In embodiments, z31 is 3. In embodiments, z31 is 4.
  • the compound has the formula: , wherein L 1 , R 2 , z2, R 3 , L 3 , L 4 , R 5 , and
  • R are as described herein.
  • the compound has the formula:
  • L 1 , R 3 , L 3 , L 4 , and R 6 are as described herein.
  • the compound has the formula:
  • L 1 , R 3 , L 3 , and L 4 are as described herein.
  • the compound has the formula:
  • the compound has the formula:
  • z31 is an integer from 0 to 4. In embodiments, z31 is 0 or 1. In embodiments, z31 is 0. In embodiments, z31 is 1. In embodiments, z31 is 2. In embodiments, z31 is 3. In embodiments, z31 is 4.
  • the compound has the formula:
  • L 1 , L 3 , and R 31 are as described herein.
  • the compound has the formula:
  • L 1 , L 3 , and R 32 are as described herein.
  • the compound has the formula:
  • R is a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R is a substituted or unsubstituted Ci-C 8 alkyl.
  • R is a substituted or unsubstituted C 1 -C 4 alkyl.
  • R i is a substituted or unsubstituted C 1 -C3 alkyl.
  • R is a substituted or unsubstituted 2 to 10 membered heteroalkyl.
  • R is a substituted or unsubstituted 2 to 8 membered heteroalkyl.
  • R is a substituted or unsubstituted 4 to 8 membered heteroalkyl.
  • R is a substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R is a substituted or unsubstituted 2 to 4 membered heteroalkyl.
  • the compound has the formula:
  • L 1 and L 4 are as described herein.
  • the compound has the formula:
  • the compound has the formula:
  • L 1 , R 3 , L 3 , and L 4 are as described herein.
  • the compound has the formula:
  • L 1 , R 3 , L 3 , R 31 , and z31 are as described herein.
  • the compound has the formula
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula: [0296] In embodiments, the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound has the formula:
  • the compound is HIJ-1094, ⁇ -1099, ⁇ -1204, HIJ-1437, HIJ-1483, or HIJ-1491.
  • the compound is HIJ-1094.
  • the compound is HIJ-1099.
  • the compound is ⁇ -1204.
  • the compound is ⁇ - 1437.
  • the compound is HIJ-1483.
  • the compound is HIJ-1491.
  • R 5 when R 5 is hydrogen R 6 is not hydrogen. In embodiments, when R 5 is hydrogen R 6 is not a substituted or unsubstituted Ci-C 6 alkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted Ci-C 6 alkyl. In embodiments, when R 5 is hydrogen R 6 is not an unsubstituted Ci-C 6 alkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted or unsubstituted C 1 -C4 alkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted Ci-C 4 alkyl. In embodiments, when R 5 is hydrogen R 6 is not an unsubstituted Ci-C 4 alkyl.
  • R 6 when R 5 is hydrogen R 6 is not a substituted or unsubstituted Ci-C 2 alkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted Ci-C 4 alkyl. In embodiments, when R 5 is hydrogen R 6 is not an unsubstituted Ci-C 4 alkyl. [0321] In embodiments, R 6 is not hydrogen. In embodiments, R 6 is not a substituted or unsubstituted Ci-C 6 alkyl. In embodiments, R 6 is not a substituted Ci-C 6 alkyl. In embodiments, R 6 is not an unsubstituted Ci-C 6 alkyl.
  • R 6 is not a substituted or unsubstituted Ci-C 4 alkyl. In embodiments, R 6 is not a substituted Ci-C 4 alkyl. In embodiments, R 6 is not an unsubstituted Ci-C 4 alkyl. In embodiments, R 6 is not a substituted or unsubstituted Ci-C 2 alkyl. In embodiments, R 6 is not a substituted Ci-C 4 alkyl. In embodiments, R 6 is not an unsubstituted Ci-C 4 alkyl.
  • R 5 is not hydrogen. In embodiments, R 5 is not a substituted or unsubstituted Ci-C 6 alkyl. In embodiments, R 5 is not a substituted Ci-C 6 alkyl. In embodiments, R 5 is not an unsubstituted Ci-C 6 alkyl. In embodiments, R 5 is not a substituted or unsubstituted Ci-C 4 alkyl. In embodiments, R 5 is not a substituted Ci-C 4 alkyl. In embodiments, R 5 is not an unsubstituted Ci-C 4 alkyl. In embodiments, R 5 is not a substituted or unsubstituted Ci-C 2 alkyl.
  • R 5 is not a substituted Ci-C 4 alkyl. In embodiments, R 5 is not an unsubstituted Ci-C 4 alkyl. [0323] In embodiments, when R 5 is hydrogen R 6 is not a 2 to 6 membered heteroalkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, when R 5 is hydrogen R 6 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, when R 5 is hydrogen R 6 is not a substituted 2 to 6 membered heteroalkyl. In
  • R when R is hydrogen R is not . In embodiments, when R is hydrogen R is not .
  • R 6 is not ⁇ . In embodiments, when R 5 is hydrogen R 6 is not ⁇
  • R when R is hydrogen R is not [0324] In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(substituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(substituted heteroalkyl). In embodiments, when R is hydrogen R is not [0324] In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-(substituted heteroalkyl). In
  • R 5 when R 5 is hydrogen R 6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, when R 5 is hydrogen R 6 is not -C(0)-0-(substituted heteroalkyl).
  • R 6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R 6 is not -C(O)- (substituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(substituted heteroalkyl).
  • R 5 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R 5 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R 5 is not -C(0)-(substituted heteroalkyl). In embodiments, R 5 is not -C(0)-0- (substituted or unsubstituted heteroalkyl). In embodiments, R 5 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R 5 is not -C(0)-0-(substituted heteroalkyl). [0326] In embodiments, R 6 is not a 2 to 6 membered heteroalkyl.
  • R 6 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, R 6 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 6 is not a substituted 2 to 6 membered heteroalkyl.
  • R 6 is not A O J ⁇ . In embodiments, R 6 is not s *A ° / . In embodiments, R 6
  • R 6 is not A ⁇ . In embodiments, R 6 is not A ⁇ . In embodiments, R° is not In embodiments, R 6 is not
  • R 5 is not a 2 to 6 membered heteroalkyl. In embodiments, R 5 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is not a 2 to 6 membered heteroalkyl.
  • R 5 is not . In embodiments, R 5
  • R 5 is not In embodiments, R 5 is not . In embodiments, R 1 is not N0 2 .
  • R 1 3 is not N0 2 .
  • the compound does not have the formula:
  • L 3 , and L 4 are as described herein.
  • the compound does not have the formula: wherein R 1 , zl, L 1 , R 2 , z2, Y,
  • L 2 , R 4 , and R 6 are as described herein. In embodiments, the compound does not have the formula:
  • R 6 is not hydrogen. In embodiments, R 6 is not a substituted or unsubstituted Ci-C 6 alkyl. In embodiments, R 6 is not a substituted Ci-C 6 alkyl. In embodiments, R 6 is not an unsubstituted Ci-C 6 alkyl. In embodiments, R 6 is not a substituted or unsubstituted C 1 -C 4 alkyl. In embodiments, R 6 is not a substituted C 1 -C 4 alkyl. In embodiments, R 6 is not an unsubstituted C 1 -C 4 alkyl.
  • R 6 is not a substituted or unsubstituted Ci-C 2 alkyl. In embodiments, R 6 is not a substituted C 1 -C 4 alkyl. In embodiments, R 6 is not an unsubstituted C 1 -C 4 alkyl. In embodiments, R 6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-(substituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R 6 is not -C(0)-0-(substituted
  • R 6 is not a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is not substituted or unsubstituted cycloalkyl.
  • R 6 is not substituted or
  • R 6 is not substituted cycloalkyl.
  • R 6 is not substituted C 3 -C 8 cycloalkyl.
  • R 6 is not unsubstituted cycloalkyl.
  • R 6 is not unsubstituted C 3 -C 8 cycloalkyl.
  • R 6 is not substituted or unsubstituted 3 to 8 membered heterocycloalkyl.
  • R 6 is not a substituted or unsubstituted 4 to 6 membered heterocycloalkyl.
  • R 6 is not a substituted or unsubstituted 5 or 6 membered heterocycloalkyl.
  • R 6 is not substituted or unsubstituted 5 membered heterocycloalkyl.
  • R 6 is not substituted or unsubstituted 6 membered heterocycloalkyl.
  • R 6 is not a substituted or unsubstituted heterocycloalkyl (e.g., substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or
  • R 6 is not a substituted or unsubstituted C 6 -Ci2 aryl. In embodiments, R 6 is not a substituted C 6 -Ci 2 aryl. In embodiments, R 6 is an unsubstituted C 6 -Ci 2 aryl. In embodiments, R 6 is not a substituted or unsubstituted C 6 -Ci 0 aryl. In embodiments, R 6 is not a substituted C 6 -Cio aryl. In embodiments, R 6 is an unsubstituted C 6 -Cio aryl. In embodiments, R 6 is an unsubstituted phenyl.
  • R 6 is not a substituted phenyl. In embodiments, R 6 is an unsubstituted naphthyl. In embodiments, R 6 is not a substituted naphthyl. In embodiments, R 6 is an unsubstituted biphenyl. In embodiments, R 6 is not a substituted biphenyl.
  • R 6 is not a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 6 is not a substituted 5 to 10 membered heteroaryl. In embodiments, R 6 is an unsubstituted 5 to 10 membered heteroaryl. In embodiments, R 6 is not a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 6 is not a substituted 5 to 6 membered heteroaryl. In embodiments, R 6 is an unsubstituted 5 to 6 membered heteroaryl. In embodiments, R 6 is not a substituted or unsubstituted 5 membered heteroaryl.
  • R 6 is not a substituted 5 membered heteroaryl. In embodiments, R 6 is an unsubstituted 5 membered heteroaryl. In embodiments, R 6 is not a substituted or unsubstituted 6 membered heteroaryl. In embodiments, R 6 is not a substituted 6 membered heteroaryl. In embodiments, R 6 is an unsubstituted 6 membered heteroaryl.
  • R 6 is not unsubstituted triazolyl. In embodiments, R 6 is not substituted triazolyl. In embodiments, R 6 is not unsubstituted tetrazolyl. In embodiments, R 6 is not substituted tetrazolyl. In embodiments, R 6 is not substituted or unsubstituted pyridyl. R 6 is not substituted or unsubstituted heteroaryl.
  • R 6 is not a substituted or unsubstituted heteroaryl such as, for example, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyranyl, substituted or unsubstituted thiopyranyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimindyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazinyl, substituted or unsubstituted thia
  • composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable salt thereof is included in a therapeutically effective amount.
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent).
  • the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount.
  • the second agent is an agent for treating asthma.
  • the second agent is an agent for treating cancer.
  • the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the second agent is an anti-inflammatory agent.
  • the second agent is an anti-autoimmune disease agent.
  • a method for treating asthma including
  • the asthma is severe asthma.
  • the asthma is acute severe asthma.
  • the asthma is moderate asthma.
  • a method for treating asthma by administering to a subject in need thereof an ⁇ 5 ⁇ 1 -inhibitor (e.g., where the ⁇ 5 ⁇ 1 -inhibitor is a compound having a formulae described herein, including embodiments thereof).
  • a method for treating asthma by administering to a subject in need thereof a therapeutically effective amount of an ⁇ 5 ⁇ 1 -inhibitor, where the ⁇ 5 ⁇ 1 -inhibitor is an ⁇ 5 ⁇ 1 -inhibitor compound having the formulae described herein, including embodiments thereof.
  • the ⁇ 5 ⁇ 1 -inhibitor compound may be a compound having a formula described herein, including embodiments thereof.
  • the ⁇ 5 ⁇ 1- inhibitor compound may be a pharmaceutical composition as described herein, including embodiments thereof.
  • the compound is ⁇ -1094, HIJ-1099, HIJ-1204, ⁇ - 1437, HIJ-1483, or HIJ-1491.
  • the cancer is ovarian cancer, bladder cancer, head and neck cancer, brain cancer, breast cancer, lung cancer, cervical cancer, liver cancer, colorectal cancer, pancreatic cancer, glioblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, renal cancer, renal cell carcinoma, non-small cell lung cancer, uterine cancer, testicular cancer, anal cancer, bile duct cancer, biliary tract cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, urinary bladder cancer, genitourinary tract cancer, endometrial cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, or prostate cancer.
  • the cancer is ovarian cancer, bladder cancer,
  • the inflammatory disease is arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Add
  • a method of treating an autoimmune disease including administering to a subject in need thereof an effective amount of a compound described herein.
  • the autoimmune disease is arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvi
  • a method of detecting the presence of ⁇ 5 ⁇ 1 integrin or inhibiting ⁇ 5 ⁇ 1 integrin activity including contacting an ⁇ 5 ⁇ 1 integrin with a compound as described herein.
  • the method includes administering a second agent (e.g. therapeutic agent). In embodiments, the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-inflammatory agent. [0347] In embodiments, the method includes detecting the presence of ⁇ 5 ⁇ 1 integrin and inhibiting ⁇ 5 ⁇ 1 integrin activity. In embodiments, the method includes detecting the presence of ⁇ 5 ⁇ 1 integrin. In embodiments, the method includes inhibiting ⁇ 5 ⁇ 1 integrin activity.
  • ⁇ 5 ⁇ 1 expression in a cell is a method of detecting ⁇ 5 ⁇ 1 expression in a cell by contacting a cell with an ⁇ 5 ⁇ 1- specific moiety (e.g., compound described herein) and allowing the o ⁇ l-specific moiety to bind to the cell. The o ⁇ l-specific moiety is detected, thereby detecting ⁇ 5 ⁇ 1 expression in a cell.
  • the detection may be performed using techniques known in the art (e.g. fluorescence detection or radiolabel detection).
  • the cell may form part of an organism (e.g. a human).
  • Embodiments contemplated herein include embodiments PI to PI 11 following.
  • Embodiment PI A compound having the formula:
  • R 1 is independently halogen
  • L 1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
  • R 2 is independently halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3, -OCH 2 X 2 , -OCHX 2 2 , -CN, -SO ⁇ R 20 , -SO v2 R 2A R 2B
  • R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety;
  • R 4 is independently hydrogen, -CX 4 3 , -CN, -COOH,
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • L 2 is unsubstituted alkyl ene
  • L 3 is a bond, -0-, -S-, -N(R 7 )-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene;
  • R 7 is hydrogen, -CN, -COOH, -CX 7 3 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
  • L 4 is -0-, -S-,-N(R 8 )-, -C(O)-, C(0)
  • R 8 is hydrogen, -CN, -COOH, -CX 8 3 , substituted or unsubstituted alkyl, or
  • R 5 and R 6 are independently hydrogen
  • substituted or unsubstituted alkyl substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • R and R 6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
  • R 9 is hydrogen, halogen, -N 3 , -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , - CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -N0 2 , -SH, -S0 2 , -S0 2 CH 3 -S0 3 H, -SO 4 H, -S0 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(0)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted;
  • Embodiment P2 The compound of embodiment PI, wherein zl is an integer from 1 to
  • Embodiment P4 The compound of any one of embodiments PI to P3, wherein
  • Embodiment P5 The compound of any one of embodiments PI to P3 having the
  • Embodiment P6 The compound of any one of embodiments PI to P5, wherein L 1 is a bond.
  • Embodiment P7 The compound of any one of embodiments PI to P6, wherein R 1 is independently halogen, -N 3 , -CF 3 , -CC1 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, - H 2 , -COOH, - CO H 2 , -SH, -SO 2 , -S0 2 CH 3 -S0 3 H, -OS0 3 H, -S0 2 NH 2 , - HNH 2 , -O H 2 , - HC(0) HNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
  • Embodiment P8 The compound of any one of embodiments PI to P6, wherein R 1 is independently halogen, -OMe, -SMe, -S0 2 Me, -S0 2 Ph, -COOH, substituted or unsubstituted Ci- C 8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubsti
  • Embodiment P9 The compound of any of embodiments PI to P8, wherein L 2 is unsubstituted Ci-C 2 alkylene.
  • Embodiment P10 The compound of any of embodiments PI to P8, wherein L 2 is unsubstituted methylene.
  • Embodiment PI 1 The compound of any of embodiments PI to P10, wherein R 4 is hydrogen.
  • Embodiment P12 The compound of any one of embodiments PI to PI 1, wherein L 3 is a bond, substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
  • Embodiment P13 The compound of any one of embodiments PI to PI 1, wherein L 3 is a bond.
  • Embodiment P14 The compound of any one of embodiments PI to PI 1, wherein L 3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P15 The compound of any one of embodiments PI to PI 1, wherein L 3 is substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment P16 The compound of any one of embodiments PI to PI 1, wherein L 3 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment PI 7 The compound of any one of embodiments 1 to 11, wherein L 3 is an oxo- substituted Ci-C 8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
  • Embodiment P18 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
  • Embodiment P19 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
  • Embodiment P20 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted Ci-C 8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment P21 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment P22 The compound of any one of embodiments PI to P17, wherein L 4 is an oxo-substituted Ci-C 8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
  • Embodiment P23 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • Embodiment P24 The compound of any one of embodiments PI to P17, wherein L 4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
  • Embodiment P25 The compound of any one of embodiments PI to P17, wherein L 4 is unsubstituted phenylene. 5
  • Embodiment P26 The compound of any one of embodimentsP 1 to P25, wherein R
  • R are independently hydrogen, , or substituted or unsubstituted
  • heterocycloalkyl substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Embodiment P27 The compound of any one of embodiments PI to P25, wherein R
  • R 6 are independently hydrogen, , substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P28 The compound of any one of embodiments PI to P25, wherein R 5 substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P29 The compound of any one of embodiments PI to P25, wherein R 6 substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P30 The compound of any one of embodiments PI to P25, wherein R
  • R 6 are independently hydrogen
  • Embodiment P31 The compound of any one of embodiments PI to P25, wherein R 5 is
  • R 6 is , u , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Embodiment P32 The compound of any one of embodiments PI to P25, wherein R 5
  • Embodiment P33 The compound of any one of embodiments PI to P25, wherein R 5 and R 6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
  • Embodiment P34 The compound of any one of embodiments PI to P25, wherein R 5 is
  • Embodiment P35 The compound of any one of embodiments PI to P25, wherein R 5 is
  • Embodiment P36 The compound of any one of embodiments PI to P25, wherein R is hydrogen and R 6 is substituted or unsubstituted heteroaryl.
  • Embodiment P37 The compound of any one of embodiments PI to P25, wherein R 5 is hydrogen and R 6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
  • Embodiment P38 The compound of any one of embodiments PI to P37, wherein R 3 is hydrogen.
  • Embodiment P39 The compound of any one of embodiments PI to P37, wherein R 3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment P40 The compound of embodiment PI, having the formula:
  • Embodiment P42 The compound of embodiment PI, having the formula:
  • Embodiment P43 The compound of embodiment PI, having the formula: f embodiment PI, having the formula:
  • Embodiment P48 The compound of embodiments PI, having the formula: 0399] Embodiment P49.
  • Embodiment P50 The compound of embodiment PI, having the formula:
  • Embodiment P51 The compound of embodiment PI, having the formula:
  • Embodiment P52 The compound of embodiment PI, having the formula:
  • Embodiment P53 The compound of embodiment PI, having the formula:

Abstract

Disclosed herein, inter alia, are inhibitors of integrin alpha 5 beta 1 and methods of using the same.

Description

INHIBITORS OF INTEGRIN ALPHA 5 BETA 1 AND METHODS OF USE
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No., 62/317,422 filed April 1, 2016, which is incorporated herein by reference in its entirety and for all purposes.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under grant numbers F32
HL112588, U19 AI070412, R01 HL102292, and U19 AI077439 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND
[0003] Despite its high prevalence, current therapeutic options for asthma are quite limited. There are a paucity of effective treatments for asthma. Pharmacological modulation of the α5β1 integrin by small molecules presents one route to test the role of the α5β1 integrin in asthma. There is a need in the art for potent, selective α5β1 integrin inhibitors. Provided herein are solutions to these and other problems in the art.
BRIEF SUMMARY OF THE INVENTION
[0004] Herein are provided, inter alia, methods for treating asthma using an α5β1 inhibitor and compositions of α5β1 inhibitors. 0005] In an aspect is provided a compound having the formula:
. R1 is independently halogen, -
Figure imgf000003_0001
-SO„iR1D,
-SOviNR1AR1B, -OSOviR1D, -NHC(0)NR1AR1B, -N(0)mi, -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0)NR1AR1B-OR1D, -NR1AS02R1D, -NR1AC(0)R1C, -NR1AC(0)ORlc, -NR1AORlc, -ONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -O- C-, -C-0-, - C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, - CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SO^R20,
-SOv2 R2AR2B, - HC(0) R2AR2B, -N(0)m2, - R2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C, - R2AC(0)OR2C, - R2AOR2C, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety. R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L2 is unsubstituted alkylene. L3 is a bond, -0-, -S-, - N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene. R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R5 and R6 are
independently hydrogen,
Figure imgf000004_0001
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S02, -S02CH3 -S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, - CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I. The symbols nl and n2 are independently an integer from 0 to 4. The symbols ml, m2, vl and v2 are independently 1 or 2. zl is an integer from 0 and 5. z2 is an integer from 0 and 9. z3 is 0 or 1. In embodiments, when R5 is hydrogen, R6 is not hydrogen.
[0006] In another aspect is provided a pharmaceutical composition including a
pharmaceutically acceptable excipient and a compound as described herein. [0007] In an aspect is provided a method for treating asthma, the method including
administering to a subject in need thereof an effective amount of a compound, or a
harmaceuticall acceptable salt thereof, having the formula:
. R1 is independently halogen,
Figure imgf000005_0001
, -SO„iR1D,
-SOviNR1AR1B, -OSOviR1D, -NHC(0)NR1AR1B, -N(0)mi, -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0R1C, - R1A0R1C, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, - C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SO^R20, -SOv2 R2AR2B,
-NHC(0) R2AR2B, -N(0)m2, - R2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, -NR2AS02R2D, - R2AC(0)R2C, -NR2AC(0)OR2C, - R2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety. R4 is independently
hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L2 is unsubstituted alkylene. L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. L4 is -0-, -S- - N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene. R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R5 and R6 are independently hydrogen,
Figure imgf000007_0001
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R5 and R6 may optionally be joined to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl. R9 is hydrogen, halogen, -N3, -CX9 3, -CHX92, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC(0) H H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, - COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, - NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, Χ 1, Χ 2, Χ 4, Χ 7, Χ 8, Χ 9, and X10 are independently -F, -CI, -Br, or -I. The symbols nl and n2 are independently an integer from 0 to 4. The symbols ml, m2, vl and v2 are independently 1 or 2. zl is an integer from 0 and 5. z2 is an integer from 0 and 9. z3 is 0 or l .
[0008] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound, or pharmaceutically acceptable salt, as described herein.
[0009] In an aspect is provided a method of treating an inflammatory disease including administering to a subject in need thereof an effective amount of a compound, or
pharmaceutically acceptable salt, as described herein. [0010] In an aspect is provided a method of treating an autoimmune disease including administering to a subject in need thereof an effective amount of a compound, or
pharmaceutically acceptable salt, as described herein.
[0011] In an aspect is provided a method of detecting the presence of α5β1 integrin or inhibiting α5β1 integrin activity, the method including contacting an α5β1 integrin with a compound, or pharmaceutically acceptable salt, as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIGS. 1A-1B. To investigate the role of α5β1 integrin in smooth muscle, wildtype (WT) mice were sensitized and challenged with ovalbumin (OVA). After intranasal
administration of ATN-161, a known α5β1 inhibitor, or a vehicle control, pulmonary resistance was measured in response to increasing doses of acetylcholine (FIG. 1 A). This experiment was repeated in an α5β1 knockout model. Mice homozygous for a conditional null (floxed) allele of itga5 were crossed to mice expressing rTTa under the control of the smooth muscle specifc a smooth muscle actin promoter and tet-0 ere and fed doxycline from conception to delete itga5 only in smooth muscle. These mice were sensitized and challenged with ovalbumin or saline, and airway hyperresponsiveness was measured in response to increasing doses of acetylcholine. Compared to littermate controls, conditional itga5 knockout mice were dramatically protected from ovalbumin-induced airway hyperresponsiveness (FIG. IB).
DETAILED DESCRIPTION
[0013] Integrins are present in nearly all multi-cellular organisms and play a conserved role in mediating cell adhesion to fixed extracellular ligands and in the maintenance of tissue integrity. In invertebrates, a surprisingly small number of integrin heterodimers mediate these diverse functions. Much has been learned about the critical in vivo functions of most members of the integrin family through the use of mice with global or conditional inactivating mutations of individual subunits and through the use of heterodimer-specific blocking monoclonal antibodies. Pharmacological modulation of the α5β1 integrin by compounds described herein may be used to treat asthma. Described herein are compounds and methods of use for α5β1 integrin inhibitors.
I. Definitions
[0014] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0015] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH20- is equivalent to -OCH2-.
[0016] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched non-cyclic carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated.
[0017] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited
by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
[0018] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched non-cyclic chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, S, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited
to: -CH2-CH2-0-CH3, -CH2-CH2- H-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 2, -S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH- N(CH3)-CH3, -0-CH3, -0-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
[0019] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2- H-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2R'- represents both -C(0)2R'- and -R'C(0)2-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0) R', -NR'R", -OR, -SR, and/or -S02R. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive.
Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
[0020] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of "alkyl" and
"heteroalkyl," respectively, wherein the carbons making up the ring or rings do not necessarily need to be bonded to a hydrogen due to all carbon valencies participating in bonds with non- hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-l,2, dione, adamantanyl, and the like. Examples of heterocycloalkyl include, but are not limited to, l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. A heterocycloalkyl moiety may include one ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include two optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include three optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include four optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include five optionally different ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may include up to 8 optionally different ring heteroatoms (e.g., O, N, S, Si, or P).
[0021] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[0022] The term "acyl" means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0023] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non- limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4- biphenyl, 1 -pyrrol yl, 2-pyrrolyl, 3 -pyrrol yl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of aryl and heteroaryl groups include pyridinyl,
pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl,
benzodioxanyl, thianaphthanyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl,
pyridopyrazinyl, quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The examples above may be substituted or unsubstituted and divalent radicals of each heteroaryl example above are non-limiting examples of heteroarylene. A heteroaryl moiety may include one ring heteroatom (e.g., O, N, or S). A heteroaryl moiety may include two optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include three optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include four optionally different ring heteroatoms (e.g., O, N, or S). A heteroaryl moiety may include five optionally different ring heteroatoms (e.g., O, N, or S). An aryl moiety may have a single ring. An aryl moiety may have two optionally different rings. An aryl moiety may have three optionally different rings. An aryl moiety may have four optionally different rings. A heteroaryl moiety may have one ring. A heteroaryl moiety may have two optionally different rings. A heteroaryl moiety may have three optionally different rings. A heteroaryl moiety may have four optionally different rings. A heteroaryl moiety may have five optionally different rings.
[0024] A fused ring heterocyloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring
heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring
heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl- cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein. [0025] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom.
[0026] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(02)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").
[0027] Each of the above terms (e.g., "alkyl," "heteroalkyl,", "cycloalkyl", "heterocycloalkyl", "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0028] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkyl ene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR, =0, = R',
=N-OR, - R'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, -C02R, -CO R'R", -OC(0)N RR", - R"C(0)R, - R'-C(0) R"R", - R"C(0)2R, - R-C( R'R"R")= R"", - R-C( R'R")= R'", -S(0)R, -S(0)2R, -S(0)2 R'R", - RS02R, - R' R"R", -O R'R",
- R'C=(0) R" R"'R"", -CN, -N02, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R, R, R", R", and R"" each preferably
independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" group when more than one of these groups is present. When R and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like). [0029] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for
example: -OR, -NR'R", -SR, -halogen, -SiRR'R", -OC(0)R, -C(0)R, -C02R, -CONR'R", -OC (0)NR'R", -NR"C(0)R, -NR'-C(0)NR"R", -NR"C(0)2R, -NR-C(NR'R"R"')=NR"", -NR-C(NR' R")= R"', -S(0)R', -S(0)2R', -S(0)2 R'R", - RS02R, - R' R"R", -O R'R",
- R'C=(0) R" R'"R"", -CN, -N02, -R, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R, R", R", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R, R", R", and R"" groups when more than one of these groups is present. [0030] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.
[0031] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR)q-U-, wherein T and U are
independently - R-, -0-, -CRR-, or a single bond, and q is an integer of from 0 to 3.
Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR-, -0-, - R-, -S-, -S(O) -, -S(0)2-, -S(0)2 R'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the
formula -(CRR)S-X'- (C"R"R")d-, where s and d are independently integers of from 0 to 3, and X' is -0-, - R'-, -S-, -S(O)-, -S(0)2-, or -S(0)2 R'-. The substituents R, R, R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0032] As used herein, the terms "heteroatom" or "ring heteroatom" are meant to include, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
[0033] A "substituent group," as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -S04H, -
S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) NH2, -NHS02H, - HC= (O)H, -NHC(0)-OH, - HOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH-S03H, -S04H, - S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, - S04H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -
NHS02H, -NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted
heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and
(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo,
halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -S04H, - S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHS02H, - NHC= (O)H, -NHC(0)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
[0034] A "size-limited substituent" or " size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[0035] A "lower substituent" or " lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl .
[0036] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0037] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Ci0 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
[0038] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Ci0 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.
[0039] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolyl sulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of
Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
[0040] Thus, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.
[0041] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
[0042] Provided herein are agents (e.g. compounds, drugs, therapeutic agents) that may be in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under select physiological conditions to provide the final agents (e.g. compounds, drugs, therapeutic agents). Additionally, prodrugs can be converted to agents (e.g. compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment. Prodrugs described herein include compounds that readily undergo chemical changes under select physiological conditions to provide agents (e.g. compounds, drugs, therapeutic agents) to a biological system (e.g. in a subject, in a cancer cell, in the extracellular space near a cancer cell).
[0043] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention. [0044] As used herein, the term "salt" refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. [0045] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute
stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0046] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0047] The term "tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
[0048] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
[0049] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. [0050] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this invention.
[0051] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[0052] The symbol "^" denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
[0053] "Analog," or "analogue" is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
[0054] The terms "a" or "an," as used herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted Ci-C2o alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted Ci-C2o alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R- substituted." Where a moiety is R- substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. [0055] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
[0056] A "detectable moiety" as used herein refers to a moiety that can be covalently or noncovalently attached to a compound or biomolecule that can be detected for instance, using techniques known in the art. In embodiments, the detectable moiety is covalently attached. The detectable moiety may provide for imaging of the attached compound or biomolecule. The detectable moiety may indicate the contacting between two compounds. Exemplary detectable moieties are fluorophores, antibodies, reactive dies, radio-labeled moieties, magnetic contrast agents, and quantum dots. Exemplary fluorophores include fluorescein, rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, and cyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68, and Copper-64. Exemplary magnetic contrast agents include gadolinium, iron oxide and iron platinum, and manganese. The detectable moiety may be covalently attached through a covalent linker to the remainder of the molecule, wherein the covalent linker forms part of the detectable moiety. Therefore, a detectable moiety may include a detectable portions (e.g. a fluorophore) and covalent linker portion. The covalent linker portion may be L12, wherein L12 is -0-, -C(O)-, -CO(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene. The covalent linker portion may be L12, wherein L12 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene.
[0057] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0058] An "α5β1 -inhibitor" as used herein refers to a composition (e.g. a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) capable of reducing the activity of α5β1 integrin when compared to a control compound (e.g. known to have no reduction in α5β1 integrin activity) or the absence of the α5β1 -inhibitor compound. An "α5β1 -inhibitor compound" refers to a compound (e.g. compounds described herein) that reduce the activity of α5β1 integrin when compared to a control, such as absence of the compound or a compound with known inactivity. An "α5β1 -inhibitor-antibody" refers to an antibody that reduces the activity of α5β1 integrin when compared to a control (e.g. the absence of the antibody). An "a5pi-inhibitor-RGD peptide" refers to a RGD-peptide that reduces the activity of α5β1 integrin when compared to a control (e.g. the absence of the peptide). [0059] An "α5β1 -specific moiety", "specific," "specifically", "specificity", or the like of a composition (e.g. a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) refers to the composition's ability to discriminate between particular molecular targets to a significantly greater extent than other proteins in the cell (e.g. a compound having specificity towards α5β1 integrin binds to α5β1 integrin whereas the same compound displays little-to-no binding to other integrins such as ανβΐ, α8β1, α2β1, ανβ3, ανβ5, or ανβό). An "α5β1 -specific compound" refers to a compound (e.g. compounds described herein) having specificity towards α5β1 integrin. An "α5β1 -specific antibody" refers to an antibody having specificity towards α5β1 integrin. An "α5β1 -specific RGD peptide" refers to a RGD peptide having specificity towards α5β1 integrin.
[0060] The terms "α5β1 -selective," "selective," or "selectivity" or the like of a compound refers to the composition's (e.g. a compound, nucleic acid, polynucleotide, peptide, protein, or antibody) ability to cause a particular action in a particular molecular target (e.g. a compound having selectivity toward α5β1 integrin would inhibit only α5β1). An "α5β1 -selective compound" refers to a compound (e.g. compounds described herein) having selectivity towards α5β1 integrin. An "α5β1 -selective antibody" refers to an antibody having selectivity towards α5β1 integrin. An "α5β1 -selective RGD peptide" refers to a RGD peptide having selectivity towards α5β1 integrin.
[0061] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymer.
[0062] A polypeptide, or a cell is "recombinant" when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g. non-natural or not wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is
recombinant.
[0063] "RGD peptide" as used herein refers to a tripeptide comprising Arg, Gly, and Asp. RGD peptides typically act as recognition sequences for integrins and in some embodiments, promote cellular adhesion via integrin binding. RGD peptides as used herein refers to naturally occurring RGD sequences, RGD mimetics (e.g. substitutions of R, G, or D with non- proteinogenic amino acids), RGD peptides covalently bound to a targeting-moiety (e.g. a molecule for targeting the peptide to a specific integrin or specific location in a cell or organism), and cyclized RGD peptides of embodiments described herein. Exemplary RGD peptides include Arg-Gly-Asp, Asp-Gly-Arg, cyclo-Gly-Arg-Gly-Asp-Ser-Pro, and KGD peptides include Cys- Asn-Thr-Leu-Lys-Gly-Asp-Cys and Asn-Thr-Leu-Lys-Gly-Asp, and those found in Ann. Rev. Cell & Dev. Biol., 1996, Nov., Vol. 12: 697-715 and Proteins, 1992 Dec; 14(4):509-15.
[0064] "Antibody" refers to a polypeptide comprising a framework region from an
immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Typically, the antigen-binding region of an antibody will be most critical in specificity and affinity of binding.
[0065] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
[0066] Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2; a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using
recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al, Nature 348:552-554 (1990)).
[0067] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies:
Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybndoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybndoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby,
Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Patent 4,946,778, U.S. Patent No. 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625, 126; 5,633,425; 5,661,016, Marks et al, Bio/Technology 10:779-783 (1992); Lonberg et al, Nature 368:856-859 (1994); Morrison,
Nature 368:812-13 (1994); Fishwild et al, Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13 :65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al, Nature 348:552-554 (1990); Marks et al, Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al, EMBO J. 10:3655-3659 (1991); and Suresh et al, Methods in Enzymology 121 :210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).
[0068] Methods for humanizing or primatizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Jones et al, Nature 321 :522-525 (1986); Riechmann et al, Nature 332:323-327 (1988); Verhoeyen et al, Science 239: 1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
[0069] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. The preferred antibodies of, and for use according to the invention include humanized and/or chimeric monoclonal antibodies.
[0070] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including
biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture. [0071] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. [0072] As defined herein, the term "activation", "activate", "activating" and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease.
[0073] As defined herein, the term "inhibition", "inhibit", "inhibiting" and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments inhibition refers means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation). [0074] "Patient" or "subject in need thereof or "subject" refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method, as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. In some embodiments, a subject is human.
[0075] "Disease" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. In some embodiments, the disease is asthma. The disease may be airway
hyperresponsiveness. The disease may be airway hyperresponsiveness in asthma. The disease may be angiogenesis. The disease may be a cancer (e.g., ovarian cancer, bladder cancer, head and neck cancer, brain cancer, breast cancer, lung cancer, cervical cancer, liver cancer, colorectal cancer, pancreatic cancer, glioblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, renal cancer, renal cell carcinoma, non-small cell lung cancer, uterine cancer, testicular cancer, anal cancer, bile duct cancer, biliary tract cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, urinary bladder cancer, genitourinary tract cancer, endometrial cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, or prostate cancer). The disease may be an
autoimmune disease (e.g., scleroderma, lupus, diabetes, or rheumatoid arthritis). The disease may be an inflammatory disease (e.g., autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto' s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet' s disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis). In some further instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin' s lymphomas (e.g., Burkitt' s, Small Cell, and Large Cell lymphomas), Hodgkin' s lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.
[0076] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren' s
syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet' s disease, Crohn' s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison' s disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. [0077] As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include breast cancer (e.g. ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g. non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma. Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget' s Disease of the Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of the pancreatic stellate cells, cancer of the hepatic stellate cells, or prostate cancer.
[0078] The term "leukemia" refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.
[0079] The term "sarcoma" generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocyte sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
[0080] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, acral- lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
[0081] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, inhibitory nucleic acid, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,
bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair- matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.
[0082] The term "aberrant" as used herein refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non- disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
[0083] A "effective amount" is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a
"therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques {see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
[0084] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
[0085] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0086] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0087] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) compatible with the preparation. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
[0088] "Co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention can be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential administration of the
compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[0089] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
[0090] "Control" or "control experiment" is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples). [0091] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
[0092] Pharmaceutical compositions provided by the present invention include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g. symptoms of asthma). Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein. [0093] As used herein "asthma" refers to any disease or condition characterized by inflammation within the circulatory system, often accompanied with wheezing, airway restriction, shortness of breath, chest tightness, and coughing. In embodiments, asthma is characterized by airway hyperresponsiveness. In embodiments, asthma is airway
hyperresponsiveness. Asthma may refer inflammation in the bronchi and bronchioles. Asthma may refer to atopic asthma. Asthma may refer to non-atopic asthma.
[0094] The compounds described herein (e.g., compound wherein R3 is not hydrogen) may be prodrugs. The term "prodrug" when referring to a prodrug described herein (e.g. α5β1 -inhibitor compound moiety bonded to a prodrug moiety) refers to the compound including the α5β1- inhibitor compound moiety and the prodrug moiety. A "prodrug moiety" is the portion of a prodrug that may be cleaved from the prodrug resulting in an increased activity of the non- prodrug moiety portion of the prodrug, for example an α5β1 -inhibitor compound having increased α5β1 -inhibitor activity relative to the prodrug of the α5β1 -inhibitor compound. In embodiments, the compounds described herein are prodrugs, wherein the prodrug moiety is the component of the compound that is not an α5β1 -inhibitor compound moiety and is released from the α5β1 -inhibitor compound moiety upon degradation of the prodrug.
[0095] In embodiments, degradation of the prodrug includes cleavage of -OR3, wherein R3 is not hydrogen. In embodiments, degradation of the prodrug includes cleavage of -R3, wherein R3 is not hydrogen. In embodiments, an α5β1 -inhibitor compound is a compound described herein wherein R3 is hydrogen and a prodrug of the α5β1 -inhibitor compound is the identical compound except R3 is not a hydrogen. A person having ordinary skill in the art would understand that the α5β1 -inhibitor compound moiety includes only those compounds compatible with the chemistry provided herein for connecting the α5β1 -inhibitor compound moiety to the prodrug moiety and for release of the α5β1 -inhibitor compound from the compound (prodrug) (e.g., in vivo). In embodiments, degradation of the prodrug releases an active agent (e.g., α5β 1 -inhibitor compound). In such compounds, the resulting active agent includes a higher level of activity compared to the level of activity of the intact prodrug.
[0096] Integrins are transmembrane proteins that mediate interactions between adhesion molecules on adjacent cells and/or the extracellular matrix (ECM). Integrins have diverse roles in several biological processes including, for example, cell migration during development and wound healing, cell differentiation, and apoptosis. Integrins typically exist as heterodimers consisting of a subunits (about 120-170 kDa in size) and β subunits (about 90-100 kDa in size). [0097] The terms "α5β ' and "α5β 1 integrin" refer to an integrin comprised of a5 subunit and a β ΐ subunit and is used according to its common, ordinary meaning. "α5β ' refers to proteins of the same or similar names, homologs, isoforms, and functional fragments thereof, so long as such fragments retain α5β1 integrin activity. The term includes any recombinant or naturally- occurring form of α5β1, or an α5β1 preprotein, or variants thereof that maintain α5β 1 activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype α5β 1). In embodiments, a5 has the protein sequence corresponding to RefSeq
P 002196.3. In embodiments, a5 has the protein sequence corresponding to the proteolytically processed mature version of RefSeq NP_002196.3. In embodiments, a5 has the amino acid sequence corresponding to the reference number GI: 93814881 1. In embodiments, βΐ has the protein sequence corresponding to RefSeq P 002202.2 In embodiments, β ΐ has the amino acid sequence corresponding to the reference number GI: 19743813.
II. Compounds
[0098] In an aspect is provided a compound having the formula:
[
Figure imgf000035_0001
0099] R1 is independently halogen, -
OCH2X1, -OCHX^, -CN, -SO„iR1D, -SCvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C( 0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)ORlc, -N R1AORlc, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -O- C-, -C-0-, - C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, - CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2,
-CN, -SO„2R2D, -SOv2NR2AR2B, -NHC (0)NR2AR2B , -N(0)m2, -NR2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C, -NR2AC(0)OR2C, -NR2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety. R4 is independently hydrogen, -CX4 3, -CN,
-COOH, -CO H2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
2 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L is unsubstituted alkylene. L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroaryl ene. R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. L4 is -0-, -S-,-N(R8)-, - C(O)-, C(0)0-, -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or
unsubstituted heteroaryl ene. R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R5 and R6 are independently hydrogen,
NH NH NR10 NR1 0
¾^ NH2 t¾^NHR9 t¾^NHR9 ¾^ NH2
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R5 and R6 may optionally be joined to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl. R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, - COOH, -CONH2, -NO2, -SH, -SO2, -S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, - NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH,
-CO H2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. Each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I. The symbols nl and n2 are independently an integer from 0 to 4. The symbols ml, m2, vl and v2 are independently 1 or 2. zl is an integer from 0 and 5. z2 is an integer from 0 and 9. z3 is 0 or 1.
[0100] In embodiments, Y is -C-C-, -C=C-, -0-C-, -C-0-, -C-0-C-,-C-S-, -S-C, or -C-S-C-. In embodiments, Y is -C-C-. In embodiments, Y is -C=C-. In embodiments, Y is -0-C-. In embodiments, Y is -C-0-. In embodiments, Y is -C-0-C-. In embodiments, Y is -C-S-. In embodiments, Y is -S-C-. In embodiments, Y is -C-S-C-. 0101] In embodiments, the compound has the formula:
Figure imgf000037_0001
[0102] In embodiments, R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -
CHO, -OH, -NH2, -COOH, -CONH2, -SH, -S02, -S02CH3 -S03H, -OS03H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety. In embodiments, R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, - CN, -CHO, -OH, -NH2, -COOH, -CONH2, -SH, -S02, -S02CH3 -S03H, -OS03H, -S02NH2, - NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0103] In embodiments, R1 is independently halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0104] In embodiments, R1 is R11 -substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), Ru-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), Ru-substituted or unsubstituted cycloalkyl (e.g.
C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11 -substituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R11- substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0105] In embodiments, R1 is R11 -substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl), R11 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11 -substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), Ru-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), Ru-substituted aryl (e.g. C6- C10 aryl or C6 aryl), or R11 -substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0106] R11 is independently halogen, -CXU 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0)NH2, - HS02H, -NHC=(0)H, - HC(0)OH, - HOH, -OCXu 3, -OCHXu 2, R12-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R12-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R12-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R12-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R12-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R12-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X11 is a halogen.
[0107] R12 is is independently halogen, -CX12 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0)NHNH2, - HC=(0)NH2,
-NHS02H, - HC=(0)H, - HC(0)OH, -NHOH, -OCX12 3, -OCHX12 2, R13-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R13-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R13- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R13-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R13- substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R13 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X12 is a halogen.
[0108] In embodiments, R1 is independently halogen, -CXl 3,
Figure imgf000039_0001
-OCXl 3, - OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOviNR1AR1B, -NHC(0)NR1AR1B, -N(0)mi, -NR1AR1B, -C( 0)R1C, -C(0)-ORlc, -C(0)NR1AR1B, -OR1D, -NR1AS02R1D, -NR1AC(0)R1C, -NR1AC(0)ORlc, or -NR1AORlc. In embodiments, R1A is R11A-substituted or unsubstituted alkyl (e.g. C C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R11A-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11A-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11A-substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R11A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1A is -CX1A3, -CN, -COOH, -C(0) H2, R11A-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci- C4 alkyl), R11A-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11A-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11A-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11A-substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R11A-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1A is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X1A is a halogen.
[0109] R11A is independently hydrogen, halogen, -CX11A 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX11A 3, -OCHX11A 2, R12A-substituted or unsubstituted alkyl (e.g. C C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R12A-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R12A- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R12A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R12A-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R12A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X11A is a halogen.
[0110] R12A is independently hydrogen, halogen, -CX12A 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX12A 3, -OCHX12A 2, R13A-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R13A-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R13A- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R13A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R13A-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R13A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X12A is a halogen.
[0111] In embodiments, R1B is R11B-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R11B-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11B-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11B-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R11B-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0112] In embodiments, R1B is -CX1B 3, -CN, -COOH, -C(0) H2, R11B-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R11B-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11B-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11B-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11B-substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R11B-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1B is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X1B is a halogen.
[0113] R11B is independently hydrogen, halogen, -CX11B 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX11B 3, -OCHX11B 2, R12B- substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R12B-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R12B- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R12B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
12B 12B
R -substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X11B is a halogen. [0114] R12B is independently hydrogen, halogen, -CX12B 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) H H2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX12B 3, -OCHX12B 2, R13B-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R13B-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R13B- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R13B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
13B 13B
R -substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
lc 11c
[0115] In embodiments, R is R -substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 lie
alkyl, or C1-C4 alkyl), R -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R lie -substituted or unsubstituted cycloalkyl (e.g.
lie
C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 lie
to 6 membered heterocycloalkyl), R -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 lie
aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0116] In embodiments, R1C is -CX1C 3, -CN, -COOH, -C(0)NH2, R11C- substituted alkyl (e.g.
lie
Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R lie -substituted cycloalkyl (e.g. C3-C8 cycloalkyl, l ie
C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), llC 1 IC
R -substituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In
1
embodiments, R is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl,
1
or 5 to 6 membered heteroaryl). X is a halogen.
[0117] R11C is independently hydrogen, halogen, -CX11C 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) HNH2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -0CX11C 3, -0CHX11C 2, R12C-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X 1 IC is a halogen. [0118] R12C is independently hydrogen, halogen, -CX12C 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX12C 3, -OCHX12C 2, R13C-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is a halogen.
[0119] In embodiments, R1D is R11D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R11D-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11D-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11D-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R11D-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0120] In embodiments, R1D is -CX1D 3, -CN, -COOH, -C(0) H2, R11D-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R11D-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R11D-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R11D-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R11D-substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R11D-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R1D is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X1D is a halogen.
[0121] R11D is independently hydrogen, halogen, -CX11D 3, -CN, -OH, -NH2, -COOH, -CONH2,
-N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX11D 3, -OCHX11D 2, R12D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R12D-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to
8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R12D- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R12D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
12D 12D
R -substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X11D is a halogen.
[0122] R12D is independently hydrogen, halogen, -CX12D 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) H H2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX12D 3, -OCHX12D 2, R13D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R13D-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R13D- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R13D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
13D 13D
R -substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X12D is a halogen.
[0123] In embodiments, R2 is R14-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R14-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0124] In embodiments, R2 is R14-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14-substituted aryl (e.g. C6-
C10 aryl or C6 aryl), or R14-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0125] R14 is independently halogen, -CX14 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX14 3, -OCHX14 2, R15-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R15-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R15 -substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R15-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R15 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R15 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X14 is a halogen. [0126] R15 is independently halogen, -CX15 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)OH, -NHOH, -OCX15 3, -OCHX15 2, R16-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R16-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R16-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R16-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R16-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X15 is a halogen.
[0127] In embodiments, R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX22, -CN, -SO„2R2D, -SOv2NR2AR2B, -NHC(0)NR2AR2B, -N(0)m2, -NR2AR2B, -C( 0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C, - R2AC(0)OR2C, or - R2AOR2C. In embodiments, R2A is R14A-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14A-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14A-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14A-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R14A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X2 is a halogen.
[0128] In embodiments, R2A is -CX2A 3, -CN, -COOH, -C(0) H2, R14A-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14A-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14A-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14A-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14A-substituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R14A-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2A is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X2A is a halogen.
[0129] R14A is independently hydrogen, halogen, -CX14A 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX14A 3, -OCHX14A 2, R15A-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R15A-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R15A- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R15A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R15A-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R15A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X14A is a halogen.
[0130] R15A is independently hydrogen, halogen, -CX15A 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) HNH2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX15A 3, -OCHX15A 2, R16A-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R16A-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16A- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R16A-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R16A-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R16A-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X15A is a halogen.
[0131] In embodiments, R2B is R14B-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14B-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14B-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14B-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R14B-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0132] In embodiments, R2B is -CX2B 3, -CN, -COOH, -C(0)NH2, R14B-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14B-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14B-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14B-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
14B 14B
R -substituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2B is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0133] R14B is independently hydrogen, halogen, -CX14B 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) H H2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX14B 3, -OCHX14B 2, R15B-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R15B-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R15B- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R15B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R15B-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R15B-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X14B is a halogen.
[0134] R15B is independently hydrogen, halogen, -CX15B 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX15B 3, -OCHX15B 2, R16B- substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R16B-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16B- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R16B-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R16B-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R16B-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X15B is a halogen. [0135] In embodiments, R is R -substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R -substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0136] In embodiments, R2C is -CX2C 3, -CN, -COOH, -C(0) H2, R14C-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R -substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R -substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is a halogen.
[0137] R14C is independently hydrogen, halogen, -CX14C 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX14C 3, -OCHX14C 2, R15C-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R -substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is a halogen.
[0138] R15C is independently hydrogen, halogen, -CX15C 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) H H2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX15C 3, -OCHX15C 2, R16C-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R16C-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16C- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R16C-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R16C-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R16C-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X is a halogen.
[0139] In embodiments, R2D is R14D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14D-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14D-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R14D-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R14D-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0140] In embodiments, R2D is -CX2D 3, -CN, -COOH, -C(0)NH2, R14D-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R14D-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R14D-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R14D-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),
R14D-substituted aryl (e.g. C6-Cio aryl or C6 aryl), or R14D-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R2D is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X2D is a halogen.
[0141] R14D is independently hydrogen, halogen, -CX14D 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S03H, -SO4H, -S02 H2, -NHNH2, -O H2, -NHC=(0) H H2, - HC=(0) H2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX14D 3, -OCHX14D 2, R15D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R15D-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R15D- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R15D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R15D-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R15D-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X14D is a halogen.
[0142] R15D is independently hydrogen, halogen, -CX15D 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX15D 3, -OCHX15D 2, R16D-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R16D-substituted or
unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R16D- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R16D-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R16D-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R16D-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X15D is a halogen.
[0143] In embodiments, R3 is R17-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R17-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R17-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R17-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R17-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R17-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R3 is hydrogen. In embodiments, R3 is an unsubstituted C1-C4 alkyl.
[0144] R3 may be substituted or unsubstituted alkyl. R3 may be substituted or unsubstituted heteroalkyl. R3 may be substituted or unsubstituted cycloalkyl. R3 may be substituted or unsubstituted heterocycloalkyl. R3 may be substituted or unsubstituted aryl. R3 may be substituted or unsubstituted heteroaryl. In embodiments, R3 is an unsubstituted methyl. In embodiments, R3 is an unsubstituted ethyl. In embodiments, R3 is an unsubstituted propyl. In embodiments, R3 is an unsubstituted isopropyl. In embodiments, R3 is an unsubstituted t-butyl. In embodiments, R3 is an unsubstituted butyl. In embodiments, R3 is an unsubstituted Ci-C6 alkyl. In embodiments, R3 is a substituted methyl. In embodiments, R3 is a substituted ethyl. In embodiments, R3 is a substituted propyl. In embodiments, R3 is a substituted isopropyl. In embodiments, R3 is a substituted t-butyl. In embodiments, R3 is a substituted butyl. In embodiments, R3 is a substituted Ci-C6 alkyl.
[0145] In embodiments, -OR3 is a prodrug moiety. In embodiments, R3 is a prodrug moiety. It will be understood that when R3 is a prodrug moiety, the reaction that removes the prodrug moiety from the remainder of a compound described herein (e.g., prodrug) may, in embodiments, also remove the oxygen directly connected to R3. In embodiments, where -OR3 is removed, an - OH may replace the -OR3.
[0146] In embodiments, R4 is R18-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R18-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R18-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R18-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R18-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R18-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R4 is hydrogen. In embodiments, R4 is R18-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl). [0147] In embodiments, R5 is hydrogen,
Figure imgf000054_0001
, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In
embodiments, R5 is hydrogen. In embodiments, R5 is hydrogen,
Figure imgf000054_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R5 is a substituted or
unsubstituted 5 to 6 membered heteroaryl. In embodiments, R5 is hydrogen,
Figure imgf000054_0003
Figure imgf000054_0004
[0148] In embodiments, R5 is R19-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R19-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R19-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R19-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R19-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R19-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0149] In embodiments, R5 is R19-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R19-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R19-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R -substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R -substituted aryl (e 6"
C10 aryl or C6 aryl), or R19-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R5 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0150] R19 is independently halogen, -CX19 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX19 3, -OCHX19 2, R20-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R20-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R20-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R20-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R20-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R20-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X19 is a halogen.
[0151] R20 is independently halogen, -CX20 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)OH, -NHOH, -OCX20 3, -OCHX20 2, R21-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R21-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R21- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R21 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R21-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R21- substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X20 is a halogen.
[0152] In embodiments, R6 is hydrogen. In embodiments, R6 is hydrogen,
Figure imgf000055_0001
, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R6 is hydrogen, , substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R6 is a substituted or nsubstituted 5 to 6 membered heteroaryl. In embodiments, R6 is hydrogen,
Figure imgf000056_0001
Figure imgf000056_0002
In embodiments, R5 is hydrogen and R6 is
Figure imgf000056_0003
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R5 is hydrogen
and R6 is
Figure imgf000056_0004
, substituted or unsubstituted alkyl
(e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). NH NH NR10
\^ H2 ¾^NHR9 ^
[0154] In embodiments, R5 is hydrogen and R6 is
Figure imgf000057_0001
substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl. In embodiments, R5 is hydrogen and R6 is
Figure imgf000057_0002
Figure imgf000057_0003
, substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci- C4 alkyl), substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5- C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered
heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0155] In embodiments, R5 and R6 are joined to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl. In embodiments, R5 and R6 are joined to form a substituted 3 to 8 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form a substituted 4 to 8 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form a substituted 5 to 6 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form a substituted 6 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form a substituted 5 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form an unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form an unsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 to 6 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form an unsubstituted 6 membered heterocycloalkyl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 membered heterocycloalkyl.
[0156] In embodiments, R5 and R6 are joined to form a substituted 5 to 10 membered heteroaryl. In embodiments, R5 and R6 are joined to form a substituted 5 to 9 membered heteroaryl. In embodiments, R5 and R6 are joined to form a substituted 5 to 6 membered heteroaryl. In embodiments, R5 and R6 are joined to form a substituted 5 membered heteroaryl. In embodiments, R5 and R6 are joined to form a substituted 6 membered heteroaryl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 to 10 membered heteroaryl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 to 9 membered heteroaryl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 to 6 membered heteroaryl. In embodiments, R5 and R6 are joined to form an unsubstituted 5 membered heteroaryl. In embodiments, R5 and R6 are joined to form an unsubstituted 6 membered heteroaryl.
[0157] In embodiments, R5 is hydrogen and R6
Figure imgf000058_0001
. In embodiments, R5 is
hydrogen and R6
Figure imgf000058_0002
. In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted or
unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted 5 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted 6 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted 5 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is a substituted 6 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is an unsubstituted 5 membered heteroaryl. In embodiments, R5 is hydrogen and R6 is an unsubstituted 6 membered heteroaryl.
[0158] In embodiments, R5 is hydrogen and R6 is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyranyl, substituted or unsubstituted thiopyranyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimindyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazinyl, substituted or unsubstituted thiazinyl, substituted or unsubstituted doxinyl, substituted or unsubstituted dithiinyl, substituted or unsubstituted azetyl, substituted or unsubstituted oxetyl, substituted or unsubstituted thietyl, substituted or unsubstituted azirinyl, substituted or unsubstituted oxirenyl or substituted or unsubstituted thienyl.
[0159] In embodiments, R5 is hydrogen and R6 is phenyl. In embodiments, R5 is hydrogen and R6 is a substituted phenyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted phenyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted triazolyl. In
embodiments, R5 is hydrogen and R6 is a substituted triazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted triazolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted tetrazolyl. In embodiments, R5 is hydrogen and R6 is a substituted tetrazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted tetrazolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyridinyl. In embodiments, R5 is hydrogen and R6 is a substituted pyridinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyridinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyrrolyl. In embodiments, R5 is hydrogen and R6 is a substituted pyrrolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyrrolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted furanyl. In embodiments, R5 is hydrogen and R6 is a substituted furanyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted furanyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thiophenyl. In embodiments, R5 is hydrogen and R6 is a substituted thiophenyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thiophenyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted imidazolyl. In embodiments, R5 is hydrogen and R6 is a substituted imidazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted imidazolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyrazolyl. In embodiments, R5 is hydrogen and R6 is a substituted pyrazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyrazolyl. In
embodiments, R5 is hydrogen and R6 is substituted or unsubstituted oxazolyl. In embodiments, R5 is hydrogen and R6 is a substituted oxazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted oxazolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thiazolyl. In embodiments, R5 is hydrogen and R6 is a substituted thiazolyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thiazolyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyranyl. In embodiments, R5 is hydrogen and R6 is a substituted pyranyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyranyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thiopyranyl. In embodiments, R5 is hydrogen and R6 is a substituted thiopyranyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thiopyranyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyrazinyl. In embodiments, R5 is hydrogen and R6 is a substituted pyrazinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyrazinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyrimindyl. In embodiments, R5 is hydrogen and R6 is a substituted pyrimindyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyrimindyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted pyridazinyl. In
embodiments, R5 is hydrogen and R6 is a substituted pyridazinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted pyridazinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted oxazinyl. In embodiments, R5 is hydrogen and R6 is a substituted oxazinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted oxazinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thiazinyl. In embodiments, R5 is hydrogen and R6 is a substituted thiazinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thiazinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted doxinyl. In embodiments, R5 is hydrogen and R6 is a substituted doxinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted doxinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted dithiinyl. In embodiments, R5 is hydrogen and R6 is a substituted dithiinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted dithiinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted azetyl. In embodiments, R5 is hydrogen and R6 is a substituted azetyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted azetyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted oxetyl. In embodiments, R5 is hydrogen and R6 is a substituted oxetyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted oxetyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thietyl. In embodiments, R5 is hydrogen and R6 is a substituted thietyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thietyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted azirinyl. In embodiments, R5 is hydrogen and R6 is a substituted azirinyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted azirinyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted oxirenyl. In embodiments, R5 is hydrogen and R6 is a substituted oxirenyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted oxirenyl. In embodiments, R5 is hydrogen and R6 is substituted or unsubstituted thienyl. In embodiments, R5 is hydrogen and R6 is a substituted thienyl. In embodiments, R5 is hydrogen and R6 is an unsubstituted thienyl. [0160] In embodiments, R6 is R22-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R22-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R22-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R22-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R22-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R22-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0161] In embodiments, R6 is R22-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R22-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R22-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R22-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R22-substituted aryl (e.g. C6- C10 aryl or C6 aryl), or R22-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R6 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0162] R22 is independently halogen, -CX22 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX22 3, -OCHX22 2, R23-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R23-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R23-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R23 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R23 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R23-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X22 is a halogen.
[0163] R23 is independently halogen, -CX23 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX23 3, -OCHX23 2, R24-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R24-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R24-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R24-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R24-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R24-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X23 is a halogen.
[0164] In embodiments, L1 is a bond. In embodiments, L1 is a substituted or unsubstituted Ci- C8 alkylene. In embodiments, L1 is a substituted or unsubstituted Ci-C6 alkylene. In
embodiments, L1 is a substituted or unsubstituted C1-C4 alkylene. In embodiments, L1 is a substituted or unsubstituted Ci-C3 alkylene. In embodiments, L1 is a substituted or unsubstituted Ci-C2 alkylene. In embodiments, L1 is a substituted or unsubstituted methylene. In embodiments, L1 is a substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L1 is a substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L1 is a substituted or unsubstituted 4 to 8 membered heteroalkylene. In embodiments, L1 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L1 is a substituted or
unsubstituted 2 membered heteroalkylene.
[0165] In embodiments, L1 is R25 -substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, C1-C4 alkylene, Ci-C3 alkylene, Ci-C2 alkylene, or methylene) or R25-substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene). In embodiments, L1 is unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, C1-C4 alkylene, Ci-C3 alkylene, Ci-C2 alkylene, or methylene) or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene). [0166] In embodiments, L1 is R25 -substituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, C1-C4 alkylene, Ci-C3 alkylene, Ci-C2 alkylene, or methylene), R25-substituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene). In embodiments, L1 is an unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, C1-C4 alkylene, C1-C3 alkylene, C1-C2 alkylene, or methylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene, or 2 membered heteroalkylene). [0167] R25 is independently halogen, -CX25 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX25 3, -OCHX25 2, R26-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R26-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R26-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R26-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R26-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R26-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X25 is a halogen.
[0168] R26 is independently halogen, -CX26 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)OH, -NHOH, -OCX26 3, -OCHX26 2, R27-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R27-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R27-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R27-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R27-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R27-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X26 is a halogen.
[0169] In embodiments, L2 is unsubstituted Ci-C8 alkylene. In embodiments, L2 is
unsubstituted C1-C4 alkylene. In embodiments, L2 is an unsubstituted Ci-C2 alkylene. In embodiments, L2 is an unsubstituted C2 alkylene. In embodiments, L2 is an unsubstituted methylene. [0170] In embodiments, L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L3 is a bond. In embodiments, L3 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L3 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), or substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L3 is a substituted or unsubstituted Ci-C8 alkylene, or substituted or
unsubstituted 2 to 8 membered heteroalkylene.
[0171] In embodiments, L3 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci- C6 alkylene, or Ci-C4 alkylene). In embodiments, L3 is a substituted or unsubstituted Ci-C8 alkylene. In embodiments, L3 is a substituted or unsubstituted Ci-C6 alkylene. In embodiments, L3 is a substituted or unsubstituted Ci-C4 alkylene. In embodiments, L3 is a substituted or unsubstituted C1-C5 alkylene. In embodiments, L3 is a substituted or unsubstituted C5 alkylene. In embodiments, L3 is a substituted C1-C5 alkylene. In embodiments, L3 is a substituted C5 alkylene. In embodiments, L3 is an unsubstituted C1-C5 alkylene. In embodiments, L3 is an unsubstituted C5 alkylene. In embodiments, L3 is a substituted or unsubstituted Ci-C4 alkylene. In
embodiments, L3 is a substituted or unsubstituted C4 alkylene. In embodiments, L3 is a substituted Ci-C4 alkylene. In embodiments, L3 is a substituted C4 alkylene. In embodiments, L3 is an unsubstituted Ci-C4 alkylene. In embodiments, L3 is an unsubstituted C4 alkylene. In embodiments, L3 is a substituted or unsubstituted Ci-C3 alkylene. In embodiments, L3 is a substituted or unsubstituted C3 alkylene. In embodiments, L3 is a substituted Ci-C3 alkylene. In embodiments, L3 is a substituted C3 alkylene. In embodiments, L3 is an unsubstituted Ci-C3 alkylene. In embodiments, L3 is an unsubstituted C3 alkylene. In embodiments, L3 is a substituted or unsubstituted Ci-C2 alkylene. In embodiments, L3 is a substituted or unsubstituted C2 alkylene. In embodiments, L3 is a substituted C1-C2 alkylene. In embodiments, L3 is a substituted C2 alkylene. In embodiments, L3 is an unsubstituted C1-C2 alkylene. In embodiments, L3 is an unsubstituted C2 alkylene.
[0172] In embodiments, L3 is a substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L3 is a substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 4 to 8 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 2 to 4 membered heteroalkylene. In embodiments, L3 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0173] In embodiments, L3 is a substituted or unsubstituted - H-(Ci-C8 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(Ci-C6 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(Ci-C5 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(Ci-C4 alkylene) -. In embodiments, L3 is a substituted - H-(Ci-C8 alkylene) -. In embodiments, L3 is a substituted - H-(Ci-C7 alkylene) -. In embodiments, L3 is a substituted - H-(Ci-C6 alkylene) -. In embodiments, L3 is a substituted - H-(Ci-C5 alkylene) -. In embodiments, L3 is a substituted - H-(Ci-C4 alkylene) -. In embodiments, L3 is an
unsubstituted - H-(Ci-C8 alkylene) -. In embodiments, L3 is an unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L3 is an unsubstituted - H-(Ci-C6 alkylene) -. In embodiments, L3 is an unsubstituted - H-(Ci-C5 alkylene) -. In embodiments, L3 is an unsubstituted - H- (Ci-C4 alkylene) -.
[0174] In embodiments, L3 is a substituted or unsubstituted - H-(C8 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(C7 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(C6 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H-(C5 alkylene) -. In embodiments, L3 is a substituted or unsubstituted - H- (C4 alkylene) -. In embodiments, L3 is a substituted - H-(C8 alkylene) -. In embodiments, L3 is a substituted - H-(C7 alkylene) -. In embodiments, L3 is a substituted - H-(C6 alkylene) -. In embodiments, L3 is a substituted - H-(C5 alkylene) -. In embodiments, L3 is a substituted - H- (C4 alkylene) -. In embodiments, L3 is an unsubstituted - H-(C8 alkylene) -. In embodiments, L3 is an unsubstituted - H-(C7 alkylene) -. In embodiments, L3 is an unsubstituted - H-(C6 alkylene) -. In embodiments, L3 is an unsubstituted - H-(C5 alkylene) -. In embodiments, L3 is an unsubstituted - H-(C4 alkylene) -.
[0175] In embodiments, L3 is a substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L3 is a substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L3 is a substituted 5 membered heteroalkylene. In embodiments, L3 is a substituted 6 membered heteroalkylene. In embodiments, L3 is a substituted 7 membered heteroalkylene. In embodiments, L3 is a substituted 8 membered heteroalkylene. In embodiments, L3 is a substituted 9 membered heteroalkylene. In embodiments, L3 is an unsubstituted 5 membered heteroalkylene. In embodiments, L3 is an unsubstituted 6 membered heteroalkylene. In embodiments, L3 is an unsubstituted 7 membered heteroalkylene. In embodiments, L3 is an unsubstituted 8 membered heteroalkylene. In embodiments, L3 is an unsubstituted 9 membered heteroalkylene.
[0176] In embodiments, L3 is an oxo-substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L3 is an oxo-substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L3 is an oxo-substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L3 is an oxo-substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L3 is an oxo-substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L3 is an oxo-substituted 5 membered heteroalkylene. In embodiments, L3 is an oxo-substituted 6 membered heteroalkylene. In embodiments, L3 is an oxo-substituted 7
membered heteroalkylene. In embodiments, L3 is an oxo-substituted 8 membered
heteroalkylene. In embodiments, L3 is an oxo-substituted 9 membered heteroalkylene. In embodiments, L3 is - H- H-C(O)-. In embodiments, L3 is - H-C(O)-. In embodiments, L3 is - H-CH2-C(0)-.
Figure imgf000066_0001
[0178] In embodiments, L3 is R28-substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), R28-substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R28-substituted or unsubstituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6
cycloalkylene), R28-substituted or unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered
heterocycloalkylene), R28-substituted or unsubstituted arylene (e.g. C6-Ci0 arylene or C6 arylene), or R28-substituted or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0179] In embodiments, L3 is R28-substituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), R28-substituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R28-substituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6 cycloalkylene), R28-substituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R28-substituted arylene (e.g. C6-Ci0 arylene or C6 arylene), or R28- substituted heteroaryl ene (e.g. 5 to 10 membered heteroaryl ene, 5 to 9 membered heteroaryl ene, or 5 to 6 membered heteroarylene).
[0180] In embodiments, L3 is an unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6 cycloalkylene), unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered
heterocycloalkylene), unsubstituted arylene (e.g. C6-Cio arylene or C6 arylene), or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0181] R28 is independently halogen, -CX28 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX28 3, -OCHX28 2, R29-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R29-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R29-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R29-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R29-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R29-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R28 is a 2 to 10 membered substituted or unsubstituted heteroalkyl. In
embodiments, R28 is a 10 membered substituted or unsubstituted heteroalkyl. In embodiments, R28 is a substituted or unsubstituted 9 membered heteroalkyl. In embodiments, R28 is a substituted or unsubstituted 8 membered heteroalkyl. In embodiments, R28 is a substituted or unsubstituted 7 membered heteroalkyl. In embodiments, R28 is a substituted or unsubstituted 6 membered heteroalkyl. In embodiments, R28 is a substituted or unsubstituted 5 membered heteroalkyl. X28 is a halogen. [0182] In embodiments, R28 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci- C6 alkylene, or C1-C4 alkylene). In embodiments, R28 is a substituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene). In embodiments, R28 is an unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene). In embodiments, R28 is a substituted or unsubstituted Ci-C8 alkylene. In embodiments, R28 is a substituted or unsubstituted Ci-C6 alkylene. In embodiments, R28 is a substituted or unsubstituted C1-C4 alkylene. In
embodiments, R28 is a substituted or unsubstituted Ci-C2 alkylene. In embodiments, R28 is a substituted or unsubstituted C2-C4 alkylene. In embodiments, R28 is a substituted or
unsubstituted C4 alkylene. In embodiments, R28 is a substituted Ci-C8 alkylene. In
embodiments, R28 is a substituted Ci-C6 alkylene. In embodiments, R28 is a substituted C1-C4 alkylene. In embodiments, R28 is a substituted Ci-C2 alkylene. In embodiments, R28 is a substituted C2-C4 alkylene. In embodiments, R28 is a substituted C4 alkylene. In embodiments, R28 is an unsubstituted Ci-C8 alkylene. In embodiments, R28 is an unsubstituted Ci-C6 alkylene. In embodiments, R28 is an unsubstituted C1-C4 alkylene. In embodiments, R28 is an unsubstituted Ci-C2 alkylene. In embodiments, R28 is an unsubstituted C2-C4 alkylene. In embodiments, R28 is an unsubstituted C4 alkylene.
[0183] In embodiments, R28 is a substituted Ci-C8 alkylene substituted with a detectable moiety. In embodiments, R28 is a substituted Ci-C6 alkylene substituted with a detectable moiety. In embodiments, R28 is a substituted C1-C4 alkylene substituted with a detectable moiety. In embodiments, R28 is a substituted Ci-C2 alkylene substituted with a detectable moiety. In embodiments, R28 is a substituted C2-C4 alkylene substituted with a detectable moiety. In embodiments, R28 is a substituted C4 alkylene substituted with a detectable moiety.
[0184] In embodiments, R28 is a substituted Ci-C8 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted Ci-C6 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted C1-C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted Ci-C2 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted C2-C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the fluorescein
isothiocyanate detectable moiety is
Figure imgf000069_0001
[0185] In embodiments, R is a substituted Ci-C8 alkylene substituted with a thiourea- detectable moiety. In embodiments, R28 is a substituted Ci-C6 alkylene substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted C1-C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted C1-C2 alkylene substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted C2-C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted Ci-C8 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted Ci-C6 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted C1-C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted Ci-C2 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted C2-C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
thiourea-fluorescein
Figure imgf000069_0002
[0186] In embodiments, R is a substituted 2 to 10 membered heteroalkyl. In embodiments, R28 is a substituted 10 membered heteroalkyl. In embodiments, R28 is a substituted 9 membered heteroalkyl. In embodiments, R28 is a substituted 8 membered heteroalkyl. In embodiments, R2 is a substituted 7 membered heteroalkyl. In embodiments, R28 is a substituted 6 membered heteroalkyl. In embodiments, R28 is a substituted 5 membered heteroalkyl. [0187] In embodiments, R28 is a substituted 2 to 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 2 to 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 2 to 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 2 to 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 9 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 7 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 5 membered heteroalkyl substituted with a detectable moiety. In
embodiments, R28 is a substituted 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 3 membered heteroalkyl substituted with a detectable moiety. In embodiments, R28 is a substituted 2 membered heteroalkyl substituted with a detectable moiety.
[0188] In embodiments, R28 is a substituted 2 to 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 2 to 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 2 to 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 2 to 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 9 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 7 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 5 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 3 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R28 is a substituted 2 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein isothiocyanate detectable moiety is bodiments, the
fluorescein isothiocyanate detectable moiety
Figure imgf000071_0001
[0189] In embodiments, R is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 10 membered heteroalkyl substituted with a thiourea- detectable moiety. In embodiments, R28 is a substituted 9 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 7 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 5 membered heteroalkyl substituted with a thiourea-detectable moiety. In
embodiments, R28 is a substituted 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 3 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R28 is a substituted 2 membered heteroalkyl substituted with a thiourea-detectable moiety.
[0190] In embodiments, R28 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 9 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 7 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 5 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 3 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R28 is a substituted 2 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
thiourea-fluorescein
Figure imgf000072_0001
[0191] In embodiments, R is a substituted 2 to 10 membered heteroalkyl. In embodiments, R28 is a substituted 10 membered heteroalkyl. In embodiments, R28 is a substituted 9 membered heteroalkyl. In embodiments, R28 is a substituted 8 membered heteroalkyl. In embodiments, R28 is a substituted 7 membered heteroalkyl. In embodiments, R28 is a substituted 6 membered heteroalkyl. In embodiments, R28 is a substituted 5 membered heteroalkyl.
[0192] R29 is independently halogen, -CX29 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX29 3, -OCHX29 2, R30-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R30-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R30-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R30-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R30-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R30-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X29 is a halogen.
[0193] In embodiments, L3 is N(R7)-. In embodiments, R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. X7 is halogen. In embodiments, R7 is hydrogen, -CN, -COOH, -CX7 3. In embodiments, R7 is hydrogen. In embodiments, R7 is R34-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R34-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R34-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R34-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R34-substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R34- substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X7 is a halogen.
[0194] In embodiments, R7 is R34-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R34-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R34-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R34-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R34-substituted aryl (e.g. C6- C10 aryl or C6 aryl), or R34-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R7 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0195] R34 is independently halogen, -CX34 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)OH, -NHOH, -OCX34 3, -OCHX34 2, R35-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R35-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R35 -substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R35-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R35 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R35 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X34 is a halogen.
[0196] R35 is independently halogen, -CX35 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX35 3, -OCHX35 2, R36-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R36-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R36-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R36-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R36-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R36-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X35 is a halogen.
[0197] In embodiments, L4 is a substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene.
Figure imgf000074_0001
[0199] In embodiments, L4 is a substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. In embodiments, L4 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), or substituted or unsubstituted
heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L4 is a substituted or unsubstituted Ci-C8 alkylene, or substituted or
unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
[0200] In embodiments, L4 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci- C6 alkylene, or C1-C4 alkylene). In embodiments, L4 is a substituted or unsubstituted Ci-C8 alkylene. In embodiments, L4 is a substituted or unsubstituted Ci-C6 alkylene. In embodiments, L4 is a substituted or unsubstituted C1-C4 alkylene. In embodiments, L4 is a substituted or unsubstituted C1-C5 alkylene. In embodiments, L4 is a substituted or unsubstituted C5 alkylene. In embodiments, L4 is a substituted C1-C5 alkylene. In embodiments, L4 is a substituted C5 alkylene. In embodiments, L4 is an unsubstituted C1-C5 alkylene. In embodiments, L4 is an unsubstituted C5 alkylene.
[0201] In embodiments, L4 is a substituted or unsubstituted - H-(Ci-C8 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(Ci-C6 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(Ci-C5 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(Ci-C4 alkylene) -. In embodiments, L4 is a substituted - H-(Ci-C8 alkylene) -. In embodiments, L4 is a substituted - H-(Ci-C7 alkylene) -. In embodiments, L4 is a substituted - H-(Ci-C6 alkylene) -. In embodiments, L4 is a substituted - H-(Ci-C5 alkylene) -. In embodiments, L4 is a substituted - H-(Ci-C4 alkylene) -. In embodiments, L4 is an
unsubstituted - H-(Ci-C8 alkylene) -. In embodiments, L4 is an unsubstituted - H-(Ci-C7 alkylene) -. In embodiments, L4 is an unsubstituted - H-(Ci-C6 alkylene) -. In embodiments, L4 is an unsubstituted - H-(Ci-C5 alkylene) -. In embodiments, L4 is an unsubstituted - H- (C1-C4 alkylene) -.
[0202] In embodiments, L4 is a substituted or unsubstituted - H-(C8 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(C7 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(C6 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H-(C5 alkylene) -. In embodiments, L4 is a substituted or unsubstituted - H- (C4 alkylene) -. In embodiments, L4 is a substituted - H-(C8 alkylene) -. In embodiments, L4 is a substituted - H-(C7 alkylene) -. In embodiments, L4 is a substituted - H-(C6 alkylene) -. In embodiments, L4 is a substituted - H-(C5 alkylene) -. In embodiments, L4 is a substituted - H- (C4 alkylene) -. In embodiments, L4 is an unsubstituted - H-(C8 alkylene) -. In embodiments, L4 is an unsubstituted - H-(C7 alkylene) -. In embodiments, L4 is an unsubstituted - H-(C6 alkylene) -. In embodiments, L4 is an unsubstituted - H-(C5 alkylene) -. In embodiments, L4 is an unsubstituted - H-(C4 alkylene) -.
[0203] In embodiments, L4 is a substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L4 is a substituted 5 membered heteroalkylene. In embodiments, L4 is a substituted 6 membered heteroalkylene. In embodiments, L4 is a substituted 7 membered heteroalkylene. In embodiments, L4 is a substituted 8 membered heteroalkylene. In embodiments, L4 is a substituted 9 membered heteroalkylene. In embodiments, L4 is an unsubstituted 5 membered heteroalkylene. In embodiments, L4 is an unsubstituted 6 membered heteroalkylene. In embodiments, L4 is an unsubstituted 7 membered heteroalkylene. In embodiments, L4 is an unsubstituted 8 membered heteroalkylene. In embodiments, L4 is an unsubstituted 9 membered heteroalkylene.
[0204] In embodiments, L4 is an oxo-substituted or unsubstituted 5 membered heteroalkylene. In embodiments, L4 is an oxo-substituted or unsubstituted 6 membered heteroalkylene. In embodiments, L4 is an oxo-substituted or unsubstituted 7 membered heteroalkylene. In embodiments, L4 is an oxo-substituted or unsubstituted 8 membered heteroalkylene. In embodiments, L4 is an oxo-substituted or unsubstituted 9 membered heteroalkylene. In embodiments, L4 is an oxo-substituted 5 membered heteroalkylene. In embodiments, L4 is an oxo-substituted 6 membered heteroalkylene. In embodiments, L4 is an oxo-substituted 7 membered heteroalkylene. In embodiments, L4 is an oxo-substituted 8 membered
heteroalkylene. In embodiments, L4 is an oxo-substituted 9 membered heteroalkylene. In embodiments, L4 is - H- H-C(O)-. In embodiments, L4 is - H-C(O)-. In embodiments, L4 is - - H-CH2-C(0)-.
[0205] In embodiments, L4 is a substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene). In embodiments, L4 is a substituted or unsubstituted 2 to 10 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 4 to 8 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L4 is a substituted or unsubstituted 2 to 4 membered heteroalkylene.
[0206] In embodiments, L4 is a substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, L4 is a substituted or unsubstituted arylene. In embodiments, L4 is a substituted or unsubstituted heteroarylene. In embodiments, L4 is a substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L4 is a substituted or unsubstituted phenylene. In embodiments, L4 is a substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, L4 is an unsubstituted phenylene. [0207] L4 may be a substituted or unsubstituted 4 to 6 membered heterocycloalkylene. L4 may be a substituted or unsubstituted 5 or 6 membered heterocycloalkylene. L4 may be substituted or unsubstituted 5 membered heterocycloalkylene. L4 may be a substituted or unsubstituted heterocycloalkylene such as substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted imidazolidinylene, substituted or unsubstituted oxazolidinylene, substituted or unsubstituted thiazolidinylene, substituted or unsubstituted dioxolanylene, substituted or unsubstituted dithiolanylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted dioxanylene, substituted or unsubstituted dithianylene, substituted or unsubstituted aziridinylene, substituted or
unsubstituted azetidinylene, substituted or unsubstituted azepinylene, substituted or unsubstituted oxiranylene, substituted or unsubstituted oxetanylene, substituted or unsubstituted
tetrahydrofuranylene, or substituted or unsubstituted tetrahydropyranylene. L4 may be a substituted or unsubstituted 6 membered heterocycloalkylene. L4 may be an unsubstituted 6 membered heterocycloalkylene. L4 may be an unsubstituted 5 membered heterocycloalkylene. L4 may be substituted or unsubstituted C3-C8 cycloalkylene. L4 may be substituted or unsubstituted 3 to 8 membered heterocycloalkylene. L4 may be unsubstituted C3-C8
cycloalkylene. L4 may be unsubstituted 3 to 8 membered heterocycloalkylene.
[0208] L4 may be substituted or unsubstituted heteroarylene. L4 may be substituted or unsubstituted 5 or 6 membered heteroarylene. L4 may be a substituted or unsubstituted heteroarylene such as, for example, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted furanylene, substituted or unsubstituted thiophenylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted pyranylene, substituted or unsubstituted thiopyranylene, substituted or unsubstituted pyrazinylene, substituted or unsubstituted pyrimindylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted oxazinylene, substituted or
unsubstituted thiazinylene, substituted or unsubstituted doxinylene, substituted or unsubstituted dithiinylene, substituted or unsubstituted azetylene, substituted or unsubstituted oxetylene, substituted or unsubstituted thietylene, substituted or unsubstituted azirinylene, substituted or unsubstituted oxirenylene or substituted or unsubstituted thienylene. L4 may be substituted or unsubstituted pyridinylene. L4 may be substituted cycloalkylene. L4 may be unsubstituted cycloalkylene. L4 may be substituted heterocycloalkylene. L4 may be unsubstituted
heterocycloalkylene. L4 may be substituted C3-C8 cycloalkylene. L4 may be unsubstituted C3-C8 cycloalkylene. L4 may be substituted 3 to 8 membered heterocycloalkylene. L4 may be unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L4 is an unsubstituted 5 to 6 membered heteroarylene.
[0209] In embodiments, L4 is R31 -substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), R31- substituted or unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R31-substituted or unsubstituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6
cycloalkylene), R31 -substituted or unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered
heterocycloalkylene), R31- substituted or unsubstituted arylene (e.g. C6-Ci0 arylene or C6 arylene), or R31- substituted or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene).
[0210] In embodiments, L4 is R31 -substituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), R31-substituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), R31-substituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6 cycloalkylene), R31- substituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), R31- substituted arylene (e.g. C6-Cio arylene or C6 arylene), or R31- substituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). In embodiments, L4 is an unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene), unsubstituted heteroalkylene (e.g. 2 to 10 membered heteroalkylene, 2 to 8 membered heteroalkylene, 4 to 8 membered heteroalkylene, 2 to 6 membered heteroalkylene, or 2 to 4 membered heteroalkylene), unsubstituted cycloalkylene (e.g. C3-C8 cycloalkylene, C4-C8 cycloalkylene, or C5-C6 cycloalkylene), unsubstituted heterocycloalkylene (e.g. 3 to 8 membered heterocycloalkylene, 4 to 8 membered
heterocycloalkylene, or 5 to 6 membered heterocycloalkylene), unsubstituted arylene (e.g. C6-Cio arylene or C6 arylene), or unsubstituted heteroarylene (e.g. 5 to 10 membered heteroarylene, 5 to 9 membered heteroarylene, or 5 to 6 membered heteroarylene). [0211] R31 is independently halogen, -CX31 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -
S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX31 3, -OCHX31 2, R32-substituted or unsubstituted alkyl
(e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R32-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R32-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R32-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R32-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R32-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X31 is a halogen.
Figure imgf000079_0001
[0214] In embodiments, R31 is a substituted or unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci- C6 alkylene, or C1-C4 alkylene). In embodiments, R31 is a substituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene). In embodiments, R31 is an unsubstituted alkylene (e.g. Ci-C8 alkylene, Ci-C6 alkylene, or C1-C4 alkylene). In embodiments, R31 is a substituted or unsubstituted Ci-C8 alkylene. In embodiments, R31 is a substituted or unsubstituted Ci-C6 alkylene. In embodiments, R31 is a substituted or unsubstituted C1-C4 alkylene. In
embodiments, R31 is a substituted or unsubstituted Ci-C2 alkylene. In embodiments, R31 is a substituted or unsubstituted C2-C4 alkylene. In embodiments, R31 is a substituted or
unsubstituted C4 alkylene. In embodiments, R31 is a substituted Ci-C8 alkylene. In
embodiments, R31 is a substituted Ci-C6 alkylene. In embodiments, R31 is a substituted C1-C4 alkylene. In embodiments, R31 is a substituted Ci-C2 alkylene. In embodiments, R31 is a substituted C2-C4 alkylene. In embodiments, R31 is a substituted C4 alkylene. In embodiments, R31 is an unsubstituted Ci-C8 alkylene. In embodiments, R31 is an unsubstituted Ci-C6 alkylene. In embodiments, R31 is an unsubstituted C1-C4 alkylene. In embodiments, R31 is an unsubstituted C1-C2 alkylene. In embodiments, R31 is an unsubstituted C2-C4 alkylene. In embodiments, R31 is an unsubstituted C4 alkylene.
[0215] In embodiments, R31 is a substituted Ci-C8 alkylene substituted with a detectable moiety. In embodiments, R31 is a substituted Ci-C6 alkylene substituted with a detectable moiety. In embodiments, R31 is a substituted C1-C4 alkylene substituted with a detectable moiety. In embodiments, R31 is a substituted Ci-C2 alkylene substituted with a detectable moiety. In embodiments, R31 is a substituted C2-C4 alkylene substituted with a detectable moiety. In embodiments, R31 is a substituted C4 alkylene substituted with a detectable moiety.
[0216] In embodiments, R31 is a substituted Ci-C8 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted Ci-C6 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted C1-C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted Ci-C2 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted C2-C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted C4 alkylene substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the fluorescein
isothiocyanate detectable moiety is bodiments, the fluorescein
isothiocyanate detectable moiety is
Figure imgf000080_0001
[0217] In embodiments, R31 is a substituted Ci-C8 alkylene substituted with a thiourea- detectable moiety. In embodiments, R31 is a substituted Ci-C6 alkylene substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted C1-C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted Ci-C2 alkylene substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted C2-C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted C4 alkylene substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted Ci-C8 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted Ci-C6 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted C1-C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted C1-C2 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted C2-C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted C4 alkylene substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
Figure imgf000081_0001
[0218] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl. In embodiments, R31 is a substituted 10 membered heteroalkyl. In embodiments, R31 is a substituted 9 membered heteroalkyl. In embodiments, R31 is a substituted 8 membered heteroalkyl. In embodiments, R31 is a substituted 7 membered heteroalkyl. In embodiments, R31 is a substituted 6 membered heteroalkyl. In embodiments, R31 is a substituted 5 membered heteroalkyl.
[0219] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 2 to 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 2 to 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 2 to 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 10 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 9 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 8 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 7 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 6 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 5 membered heteroalkyl substituted with a detectable moiety. In
embodiments, R31 is a substituted 4 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 3 membered heteroalkyl substituted with a detectable moiety. In embodiments, R31 is a substituted 2 membered heteroalkyl substituted with a detectable moiety.
[0220] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 2 to 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 2 to 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 2 to 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 10 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 9 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 8 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 7 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 6 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 5 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 4 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 3 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, R31 is a substituted 2 membered heteroalkyl substituted with a fluorescein isothiocyanate detectable moiety. In embodiments, the
fluorescein isothiocyanate detectable moiety is bodiments, the
fluorescein isothiocyanate detectable moiety
Figure imgf000082_0001
[0221] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 10 membered heteroalkyl substituted with a thiourea- detectable moiety. In embodiments, R31 is a substituted 9 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 8 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 7 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 6 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 5 membered heteroalkyl substituted with a thiourea-detectable moiety. In
embodiments, R31 is a substituted 4 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 3 membered heteroalkyl substituted with a thiourea-detectable moiety. In embodiments, R31 is a substituted 2 membered heteroalkyl substituted with a thiourea-detectable moiety.
[0222] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 2 to 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 2 to 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 2 to 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 10 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 9 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 8 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 7 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 6 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 5 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 4 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 3 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, R31 is a substituted 2 membered heteroalkyl substituted with a thiourea-fluorescein detectable moiety. In embodiments, the
thiourea-fluorescein
Figure imgf000083_0001
[0223] In embodiments, R31 is R32-substituted or unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl). In embodiments, R31 is R32-substituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl). In embodiments, R31 is an unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl). [0224] In embodiments, R31 is R32-substituted or unsubstituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is R32-substituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is an unsubstituted heteroalkyl (e.g., 2 to 10 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R31 is R32-substituted or unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R31 is R32-substituted or unsubstituted 2 to 9 membered heteroalkyl. In embodiments, R31 is R32-substituted or unsubstituted 6 to 9 membered
heteroalkyl. [0225] In embodiments, R31 is R32-substituted or unsubstituted cycloalkyl (e.g., C3-C8
cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R31 is R32-substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R31 is an unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).
[0226] In embodiments, R31 is R32-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R31 is R32-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R31 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl).
[0227] In embodiments, R31 is R32-substituted or unsubstituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In embodiments, R31 is R32-substituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In embodiments, R31 is an unsubstituted aryl (e.g., C6-Ci0 aryl, C10 aryl, or phenyl).
[0228] In embodiments, R31 is R32-substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R31 is R32-substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R31 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0229] In embodiments, R31 is a substituted 2 to 10 membered heteroalkyl. In embodiments, R31 is a substituted 10 membered heteroalkyl. In embodiments, R31 is a substituted 9 membered heteroalkyl. In embodiments, R31 is a substituted 8 membered heteroalkyl. In embodiments, R31 is a substituted 7 membered heteroalkyl. In embodiments, R31 is a substituted 6 membered heteroalkyl. In embodiments, R31 is a substituted 5 membered heteroalkyl.
[0230] R32 is independently halogen, -CX32 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX32 3, -OCHX32 2, R33-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R33-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R33 -substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R33-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R33 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R33 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X32 is a halogen. [0231] In embodiments, R32 is R33 -substituted or unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 is R33 -substituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl). In embodiments, R32 is an unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl).
[0232] In embodiments, R32 is R33 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R32 is R33 -substituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R32 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R32 is R33 -substituted or unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R32 is an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R32 is R33 -substituted 2 to 6 membered heteroalkyl.
[0233] In embodiments, R32 is R33 -substituted or unsubstituted cycloalkyl (e.g., C3-Ci0 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 is R33-substituted cycloalkyl (e.g., C3-Cio cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 is an unsubstituted cycloalkyl (e.g., C3-Cio cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R32 is an unsubstituted C3-Cio cycloalkyl. In embodiments, R32 is substituted or unsubstituted adamantanyl. [0234] In embodiments, R32 is R33 -substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R32 is R33-substituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R32 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl).
[0235] In embodiments, R32 is R33 -substituted or unsubstituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In embodiments, R32 is R33-substituted aryl (e.g., C6-Ci0 aryl, C10 aryl, or phenyl). In embodiments, R32 is an unsubstituted aryl (e.g., C6-Ci0 aryl, C10 aryl, or phenyl).
[0236] In embodiments, R32 is R33 -substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R32 is R33 -substituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R32 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
Figure imgf000086_0001
[0239] In embodiments, R is an unsubstituted alkyl (e.g., Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl). In embodiments, R33 is an unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl). In embodiments, R33 is an unsubstituted cycloalkyl (e.g., C3-C10 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In embodiments, R33 is an unsubstituted C3-C10 cycloalkyl. In embodiments, R33 is substituted or unsubstituted adamantanyl. In embodiments, R33 is an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl). In embodiments, R33 is an unsubstituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In embodiments, R33 is R33-substituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In embodiments, R33 is an unsubstituted aryl (e.g., C6-Cio aryl, C10 aryl, or phenyl). In
embodiments, R33 is an unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R33 is independently oxo or H2.
[0240] In embodiments, L4 is -N(R8)- In embodiments, R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In embodiments, R8 is hydrogen, -CN, -COOH, -CX8 3. In embodiments, R8 is hydrogen. In embodiments, R8 is R37-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R37- substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R37-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R37-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R37- substituted or unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or R37-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X8 is a halogen.
[0241] In embodiments, R8 is R37-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R37-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R37-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R37-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R37-substituted aryl (e.g. C6- C10 aryl or C6 aryl), or R37-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R8 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0242] R37 is independently halogen, -CX37 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX37 3, -OCHX37 2, R38-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R38-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R38-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R38-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R38-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R38-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X37 is a halogen.
[0243] R38 is independently halogen, -CX38 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, -NHOH, -OCX38 3, -OCHX38 2, R39-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R39-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R39-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R39-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R39-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R39-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X38 is a halogen.
[0244] In embodiments, R5 is hydrogen,
Figure imgf000088_0001
In embodiments, R9 is R40-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci- C4 alkyl), R40-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R40-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R40-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), R40-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R40- substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0245] In embodiments, R9 is R40-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R40-substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R40-substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R40-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R40-substituted aryl (e.g. C6- Cio aryl or C6 aryl), or R40-substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R9 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or Ci-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0246] R40 is independently halogen, -CX40 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX40 3, -OCHX40 2, R41-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R41-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R41- substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R41 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R41-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R41- substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X40 is a halogen.
[0247] R41 is independently halogen, -CX41 3, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, - S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, - NHC=(0)H, -NHC(0)OH, -NHOH, -OCX41 3, -OCHX41 2, R42-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R42-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R42-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R42-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R42-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R42-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X41 is a halogen.
[0248] In embodiments, R10 is R43-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R43-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R43-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R43 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R43 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R43 -substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0249] In embodiments, R10 is R43-substituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R43 -substituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R43 -substituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R43-substituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R43-substituted aryl (e.g. C6- C10 aryl or C6 aryl), or R43 -substituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R10 is an unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0250] R43 is independently halogen, -CX43 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, -
S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX43 3, -OCHX43 2, R44-substituted or unsubstituted alkyl
(e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R44-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R44-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R44-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R44-substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R44-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X43 is a halogen.
[0251] R44 is independently halogen, -CX44 3, -CN, -OH, - H2, -COOH, -CO H2, -N02, -SH, - S03H, -SO4H, -S02 H2, - HNH2, -O H2, - HC=(0) HNH2, - HC=(0) H2, - HS02H, - HC=(0)H, - HC(0)OH, - HOH, -OCX44 3, -OCHX44 2, R45-substituted or unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), R45-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), R45-substituted or unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R45 -substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R45 -substituted or unsubstituted aryl (e.g. C6-Cio aryl or C6 aryl), or R45-substituted or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). X44 is a halogen. [0252] R13, R13A, R13B, R13C, R13D, R16, R16A, R16B, R16C, R16D, R17, R18, R21, R24, R27, R30, R33, R36, R39, R42, and R45 are independently halogen, -CX3, -CN, -OH, -NH2, -COOH,
-CONH2, -N02, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0)NH2, -NHS02H, -NHC=(0)H, -NHC(0)OH, -NHOH, -OCX3, -OCHX2,
unsubstituted alkyl (e.g. Ci-C8 alkyl, Ci-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 membered
heterocycloalkyl), unsubstituted aryl (e.g. C6-Ci0 aryl or C6 aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).
[0253] In embodiments, X, X1, X2, X4, X7, X8, X9, X10, X11, X11A, X11B, X11C, X11D, X12, X12A,
V12B V12C V12D v14 V14A V14B V14C V14D v15 V15A V15B V15C V15D v19 v20 v22 v23 v25
X26, X28, X29, X31, X32, X34, X35, X37, X38, X40, X41, X43, and X44 are independently -F, -CI, -Br, or -I. In embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In embodiments, X1 is -F. In embodiments, X1 is -CI. In embodiments, X1 is -Br. In embodiments, X1 is -I. In embodiments, X2 is -F. In embodiments, X2 is -CI. In embodiments, X2 is -Br. In embodiments, X2 is -I. In embodiments, X4 is -F. In embodiments, X4 is -CI. In embodiments, X4 is -Br. In embodiments, X4 is -I. In embodiments, X7 is -F. In embodiments, X7 is -CI. In embodiments, X7 is -Br. In embodiments, X7 is -I. In embodiments, X8 is -F. In embodiments, X8 is -CI. In embodiments, X8 is -Br. In embodiments, X8 is -I. In embodiments, X9 is -F. In embodiments, X9 is -CI. In embodiments, X9 is -Br. In embodiments, X9 is -I. In embodiments, X10 is -F. In embodiments, X10 is -CI. In embodiments, X10 is -Br. In embodiments, X10 is -I. In embodiments, X11 is -F. In embodiments, X11 is -CI. In
embodiments, X11 is -Br. In embodiments, X11 is -I. In embodiments, X12 is -F. In
embodiments, X12 is -CI. In embodiments, X12 is -Br. In embodiments, X12 is -I. In
embodiments, X14 is -F. In embodiments, X14 is -CI. In embodiments, X14 is -Br. In
embodiments, X14 is -I. In embodiments, X15 is -F. In embodiments, X15 is -CI. In
embodiments, X15 is -Br. In embodiments, X15 is -I.
[0254] In embodiments, X19 is -F. In embodiments, X19 is -CI. In embodiments, X19 is -Br. In embodiments, X19 is -I. In embodiments, X20 is -F. In embodiments, X20 is -CI. In
20 20 22
embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F. In
22 22 22
embodiments, X is -CI. In embodiments, X is -Br. In embodiments, X is -I. In
23 23 23
embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
23 25 25
embodiments, X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
embodiments, X25 is -Br. In embodiments, X25 is -I. In embodiments, X26 is -F. In
embodiments, X26 is -CI. In embodiments, X26 is -Br. In embodiments, X26 is -I. In
28 28 28
embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
28 29 29
embodiments, X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
29 29 31
embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F. In
embodiments, X31 is -CI. In embodiments, X31 is -Br. In embodiments, X31 is -I. In
32 32 32
embodiments, X is -F. In embodiments, X is -CI. In embodiments, X is -Br. In
32 34 34
embodiments, X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
embodiments, X34 is -Br. In embodiments, X34 is -I. In embodiments, X35 is -F. In
embodiments, X35 is -CI. In embodiments, X35 is -Br. In embodiments, X35 is -I. In
embodiments, X37 is -F. In embodiments, X37 is -CI. In embodiments, X37 is -Br. In
37 38 38
embodiments, X is -I. In embodiments, X is -F. In embodiments, X is -CI. In
38 38 40
embodiments, X is -Br. In embodiments, X is -I. In embodiments, X is -F. In 40 ·
embodiments, X is -CI. In embodiments, X4U is -Br. In embodiments, Χ 4υ0 is -I. In
embodiments, X41 is -F. In embodiments, X41I i ·s -CI. In embodiments, X41 is -Br. In
embodiments, X41 is -I. In embodiments, X4j is -F. In embodiments, X43 is -CI. In
embodiments, X43 is -Br. In embodiments, X4j is -I. In embodiments, X44 is -F. In
44
embodiments, X is -CI. In embodiments, X44 is -Br. In embodiments, X44 is -I
[0255] In embodiments, X11A is -F. In embodiments, XiiA is -CI. In embodiments, XiiA is -Br In embodiments, X1 is -I. In embodiments, X is -F. In embodiments, X1 12AA i ·s -CI. In
12A
embodiments, X s -Br. In embodiments, X is -I. In embodiments, Xi 144AA i ·s -F. In
14A
embodiments, X s -CI. In embodiments, X is -Br. In embodiments, Xi 144AA i ·s -I. In embodiments,
Figure imgf000093_0001
-F. In embodiments, Xi3A is -CI. In embodiments, Xi3A is -Br. In
15A
embodiments, X -I. In embodiments, X11B is -F. In embodiments, X11B is -CI. In
11B
embodiments, X -Br. In embodiments, X11B is -I. In embodiments, X12B is -F. In
12B
embodiments, X -CI. In embodiments, X12B is -Br. In embodiments, X12B is -I. In
14B
embodiments, X -F. In embodiments, X14B is -CI. In embodiments, X14B is -Br. In
Λ4Β
embodiments, X -I. In embodiments, X15B is -F. In embodiments, X15B is -CI. In
15B
embodiments, X -Br. In embodiments, Xl3B is -I. In embodiments, X11C is -F. In
lie
embodiments, X -CI. In embodiments, X11C is -Br. In embodiments, X11C is -I. In embodiments, X 12C
-F. In embodiments, X12C is -CI. In embodiments, X12C is -Br. In embodiments, X 12C
-I. In embodiments, X14C is -F. In embodiments, X14C is -CI. In embodiments, X rl4C
-Br. In embodiments, X14C is -I. In embodiments, X15C is -F. In embodiments, X 15C
-CI. In embodiments, Xl3C is -Br. In embodiments, X15C is -I. In
11D
embodiments, X -F. In embodiments, X11D is -CI. In embodiments, X11D is -Br. In
11D
embodiments, X -I. In embodiments, X12D is -F. In embodiments, X12D is -CI. In
12D
embodiments, X s -Br. In embodiments, X is -I. In embodiments, X1 144LDI i ·s -F. In
Λ4Ό
embodiments, X s -CI. In embodiments, X is -Br. In embodiments, Xi 144UD i ·s -I. In
15D
embodiments, X s -F. In embodiments, X is -CI. In embodiments, Χ13υ is -Br. In
15D
embodiments, X s -I.
[0256] In embodiments, nl and n2 are independently an integer from 0 to 4. In embodiments, nl and n2 are independently an integer from 0 to 3. In embodiments, nl is 0. In embodiments, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments, nl is 4. In embodiments, n2 is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments, n2 is 3. In embodiments, n2 is 4. In embodiments, ml, m2, vl and v2 are independently 1 or 2. In embodiments, ml is 1 or 2. In embodiments, ml is 1. In embodiments, ml is 2. In embodiments, m2 is 1 or 2. In embodiments, m2 is 1. In embodiments, m2 is 2. In embodiments, vl is 1 or 2. In embodiments, vl is 1. In embodiments, vl is 2. In embodiments, v2 is 1 or 2. In embodiments, v2 is 1. In embodiments, v2 is 2.
[0257] In embodiments, zl is an integer from 0 to 5. In embodiments, zl is an integer from 1 to 5. In embodiments, zl is an integer from 2 to 5. In embodiments, zl is an integer from 3 to 5. In embodiments, zl is 4 or 5. In embodiments, zl is an integer from 1 to 3. In embodiments, zl is 0. In embodiments, zl is 1. In embodiments, zl is 2. In embodiments, zl is 3. In
embodiments, zl is 4. In embodiments, zl is 5. In embodiments, z2 is an integer from 0 to 9. In embodiments, z2 is an integer from 1 to 9. In embodiments, z2 is an integer from 2 to 9. In embodiments, z2 is an integer from 0 to 5. In embodiments, z2 is an integer from 1 to 5. In embodiments, z2 is an integer from 2 to 5. In embodiments, z2 is an integer from 3 to 5. In embodiments, z2 is 4 or 5. In embodiments, z2 is an integer from 1 to 3. In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. In embodiments, z2 is 6. In embodiments, z2 is 7. In embodiments, z2 is 8. In embodiments, z2 is 9.
[0258] In embodiments, where L3 is substituted or unsubstituted arylene, z3 is 1. In embodiments, where L3 is substituted or unsubstituted arylene, z3 is 0. In embodiments, where L3 is substituted or unsubstituted heteroarylene, z3 is 1. In embodiments, where L3 is substituted or unsubstituted heteroarylene, z3 is 0.
[0259] In embodiments, the compound has the formula
Figure imgf000094_0001
wherein RAZL R2, Z2, I.1, L L3
, and R6 are as described herein.
[0260] In embodiments, the compound has the formula
Figure imgf000094_0002
R5, and R6 are as described herein. Ring A is a substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. [0261] Ring A may be substituted or unsubstituted cycloalkylene. Ring A may be substituted or unsubstituted C3-C8 cycloalkylene. Ring A may be substituted cycloalkylene. Ring A may be substituted C3-C8 cycloalkylene. Ring A may be unsubstituted cycloalkylene. Ring A may be unsubstituted C3-C8 cycloalkylene. [0262] Ring A may be substituted or unsubstituted 3 to 8 membered heterocycloalkylene.
Ring A may be a substituted or unsubstituted 4 to 6 membered heterocycloalkylene. Ring A may be a substituted or unsubstituted 5 or 6 membered heterocycloalkylene. Ring A may be substituted or unsubstituted 5 membered heterocycloalkylene. Ring A may be substituted or unsubstituted 6 membered heterocycloalkylene. In embodiments, Ring A is a substituted or unsubstituted heterocycloalkylene (e.g., substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted imidazolidinylene, substituted or unsubstituted oxazolidinylene, substituted or unsubstituted thiazolidinylene, substituted or unsubstituted dioxolanylene, substituted or unsubstituted dithiolanylene, substituted or unsubstituted piperidinylene, substituted or unsubstituted morpholinylene, substituted or unsubstituted dioxanylene, substituted or unsubstituted dithianylene, substituted or unsubstituted aziridinylene, substituted or
unsubstituted azetidinylene, substituted or unsubstituted azepinylene, substituted or unsubstituted oxiranylene, substituted or unsubstituted oxetanylene, substituted or unsubstituted
tetrahydrofuranylene, or substituted or unsubstituted tetrahydropyranylene.
[0263] In embodiments, Ring A is a substituted or unsubstituted C6-Ci2 arylene. In embodiments, Ring A is a substituted C6-Ci2 arylene. In embodiments, Ring A is an
unsubstituted C6-Ci2 arylene. In embodiments, Ring A is a substituted or unsubstituted C6-Ci0 arylene. In embodiments, Ring A is a substituted C6-Cio arylene. In embodiments, Ring A is an unsubstituted C6-Cio arylene. In embodiments, Ring A is an unsubstituted phenylene. In embodiments, Ring A is a substituted phenylene. In embodiments, Ring A is an unsubstituted naphthylene. In embodiments, Ring A is a substituted naphthylene. In embodiments, Ring A is an unsubstituted biphenyl. In embodiments, Ring A is a substituted biphenyl.
[0264] In embodiments, Ring A is a substituted or unsubstituted 5 to 10 membered
heteroarylene. In embodiments, Ring A is a substituted 5 to 10 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted 5 to 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 to 6 membered heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 5 membered heteroarylene. In embodiments, Ring A is a substituted 5 membered heteroarylene. In embodiments, Ring A is an unsubstituted 5 membered heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 6 membered heteroarylene. In embodiments, Ring A is a substituted 6 membered heteroarylene. In embodiments, Ring A is an unsubstituted 6 membered heteroarylene.
[0265] Ring A may be unsubstituted triazolylene. Ring A may be substituted triazolylene. Ring A may be unsubstituted tetrazolylene. Ring A may be substituted tetrazolylene. In embodiments, Ring A is substituted or unsubstituted pyridylene. Ring A may be substituted or unsubstituted heteroarylene. Ring A may be a substituted or unsubstituted heteroarylene such as, for example, substituted or unsubstituted pyridinylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted furanylene, substituted or unsubstituted thiophenylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyrazolylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted pyranylene, substituted or unsubstituted thiopyranylene, substituted or unsubstituted
pyrazinylene, substituted or unsubstituted pyrimindylene, substituted or unsubstituted pyridazinylene, substituted or unsubstituted oxazinylene, substituted or unsubstituted
thiazinylene, substituted or unsubstituted doxinylene, substituted or unsubstituted dithiinylene, substituted or unsubstituted azetylene, substituted or unsubstituted oxetylene, substituted or unsubstituted thietylene, substituted or unsubstituted azirinylene, substituted or unsubstituted oxirenylene or substituted or unsubstituted thienylene. Ring A may be substituted or
unsubstituted pyridinylene. 0266] In embodiments, the compound has the formula:
Figure imgf000096_0001
as described herein. 0267] In embodiments, the compound has the formula:
Figure imgf000096_0002
R2, Z2, L1, L3, L4, and R6 are as described herein.
[0268] In embodiments, the compound has the formula: L3— L4— NR5R6
(R2)z2 R2, z2, Y, R3, R4, L1, L2, L3
L4, R5, and R6 are as described herein. R1 , R1 2, R1 3, R1 4, and R1 5 are each independently a moiety of R1 as described herein, including in embodiments.
[0269] In some embodiments, a compound as described herein may include multiple instances of R1, R2, and/or other variables. In such embodiments, each variable may optional be different and be appropriately labeled to distinguish each group for greater clarity. For example, where each R1 and/or R2 is different, they may be referred to, for example, as R1 J, R1 2, R1 3, R1 4, R1 5, R2 R2 2, R2 3, R2 4, R2 5, R2 6, R2 7, R2 8, R2 9, respectively, wherein the definition of R1 is assumed by Ru, R1 2, R1 3, R1 4, R1 5; R2 is assumed by R2 \ R2 2, R2 3, R2 4, R2 5, R2 6, R2 7, R2 8, R2 9. The variables used within a definition of R1, R2, and/or other variables that appear at multiple instances and are different may similarly be appropriately labeled to distinguish each group for greater clarity. In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, or table).
[0270] In embodiments,
Figure imgf000097_0001
has the In
embodiments,
Figure imgf000097_0002
has the formula In embodiments,
Figure imgf000097_0003
has the formula: In embodiments, has the has the formula:
Figure imgf000098_0001
[0271] In embodiments, the compound has the formula:
Figure imgf000098_0002
wherein R2, z2, L1, L3, and L4 are as described herein.
[0272] In embodiments, the compound has the formula:
Figure imgf000098_0003
wherein R2, z2, L1, L3, and
R31 are as described herein and z31 is an integer from 0 to 4. In embodiments, z31 is 0 or 1. In embodiments, z31 is 0. In embodiments, z31 is 1. In embodiments, z31 is 2. In embodiments, z31 is 3. In embodiments, z31 is 4.
[0273] In embodiments, the compound has the formula:
Figure imgf000099_0001
, wherein L1, R2, z2, R3, L3, L4, R5, and
R are as described herein.
[0274] In embodiments, the compound has the formula:
Figure imgf000099_0002
, wherein L1, R3, L3, L4, and R6 are as described herein.
[0275] In embodiments, the compound has the formula:
Figure imgf000099_0003
, wherein L1, R3, L3, and L4 are as described herein.
[0276] In embodiments, the compound has the formula:
Figure imgf000099_0004
s wherein L1, L3, and L4 are as described herein. [0277] In embodiments, the compound has the formula:
Figure imgf000100_0001
, wherein L1, L3, and R31 are as described herein and z31 is an integer from 0 to 4. In embodiments, z31 is 0 or 1. In embodiments, z31 is 0. In embodiments, z31 is 1. In embodiments, z31 is 2. In embodiments, z31 is 3. In embodiments, z31 is 4.
[0278] In embodiments, the compound has the formula:
Figure imgf000100_0002
wherein L1, L3, and R31 are as described herein.
[0279] In embodiments, the compound has the formula:
Figure imgf000100_0003
wherein L1, L3, and R32 are as described herein.
[0280] In embodiments, the compound has the formula:
Figure imgf000101_0001
wherein L1, L3, and R32 are as described herein. In embodiments, R is a substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In embodiments, R is a substituted or unsubstituted Ci-C8 alkyl. In
32
embodiments, R is a substituted or unsubstituted C1-C4 alkyl. In embodiments, Ri is a substituted or unsubstituted C1-C3 alkyl. In embodiments, R is a substituted or unsubstituted 2 to 10 membered heteroalkyl. In embodiments, R is a substituted or unsubstituted 2 to 8 membered heteroalkyl. In embodiments, R is a substituted or unsubstituted 4 to 8 membered heteroalkyl. In embodiments, R is a substituted or unsubstituted 2 to 6 membered heteroalkyl.
In embodiments, R is a substituted or unsubstituted 2 to 4 membered heteroalkyl. [0281] In embodiments, the compound has the formula:
Figure imgf000101_0002
, wherein L1 and L4 are as described herein.
[0282] In embodiments, the compound has the formula:
Figure imgf000101_0003
, wherein L1, R3, L3, L4, R5, and R6 are as described herein. [0283] In embodiments, the compound has the formula:
Figure imgf000102_0001
wherein L1, R3, L3, and L4 are as described herein.
[0284] In embodiments, the compound has the formula:
Figure imgf000102_0002
, wherein L1, R3, L3, R31, and z31 are as described herein.
[0285] In embodiments, the compound has the formula
Figure imgf000102_0003
Figure imgf000103_0001
[0286] In embodiments, the compound has the formula:
Figure imgf000103_0002
Figure imgf000104_0001
102 [0289] In embodiments, the compound has the formula:
Figure imgf000105_0001
[0290] In embodiments, the compound has the formula:
Figure imgf000105_0002
[0291] In embodiments, the compound has the formula:
Figure imgf000105_0003
[0292] In embodiments, the compound has the formula:
Figure imgf000105_0004
[0293] In embodiments, the compound has the formula:
Figure imgf000105_0005
[0294] In embodiments, the compound has the formula:
Figure imgf000105_0006
[0295] In embodiments, the compound has the formula:
Figure imgf000105_0007
[0296] In embodiments, the compound has the formula:
Figure imgf000106_0001
[0297] In embodiments, the compound has the formula:
Figure imgf000106_0002
[0298] In embodiments, the compound has the formula:
Figure imgf000106_0003
[0299] In embodiments, the compound has the formula:
Figure imgf000106_0004
[0300] In embodiments, the compound has the formula:
Figure imgf000106_0005
[0301] In embodiments, the compound has the formula:
Figure imgf000107_0001
[0302] In embodiments, the compound has the formula:
Figure imgf000107_0002
[0303] In embodiments, the compound has the formula:
Figure imgf000107_0003
In embodiments, the compound has the formula:
Figure imgf000107_0004
[0305] In embodiments, the compound has the formula:
Figure imgf000107_0005
[0306] In embodiments, the compound has the formula:
Figure imgf000107_0006
[0307] In embodiments, the compound has the formula:
Figure imgf000108_0001
[0308] In embodiments, the compound has the formula:
Figure imgf000108_0002
[0309] In embodiments, the compound has the formula:
Figure imgf000108_0003
[0310] In embodiments, the compound has the formula:
Figure imgf000108_0004
[0311] In embodiments, the compound has the formula:
Figure imgf000108_0005
[0312] In embodiments, the compound has the formula:
Figure imgf000108_0006
[0313] In embodiments, the compound has the formula:
Figure imgf000108_0007
[0314] In embodiments, the compound has the formula:
Figure imgf000109_0001
[0315] In embodiments, the compound has the formula:
Figure imgf000109_0002
In embodiments, the compound has the formula:
Figure imgf000109_0003
[0317] In embodiments, the compound has the formula:
Figure imgf000109_0004
[0318] In embodiments, the compound has the formula:
Figure imgf000110_0001
[0319] In embodiments, the compound is HIJ-1094, ΗΠ-1099, ΗΠ-1204, HIJ-1437, HIJ-1483, or HIJ-1491. In embodiments, the compound is HIJ-1094. In embodiments, the compound is HIJ-1099. In embodiments, the compound is ΗΠ-1204. In embodiments, the compound is ΗΠ- 1437. In embodiments, the compound is HIJ-1483. In embodiments, the compound is HIJ-1491.
[0320] In embodiments, when R5 is hydrogen R6 is not hydrogen. In embodiments, when R5 is hydrogen R6 is not a substituted or unsubstituted Ci-C6 alkyl. In embodiments, when R5 is hydrogen R6 is not a substituted Ci-C6 alkyl. In embodiments, when R5 is hydrogen R6 is not an unsubstituted Ci-C6 alkyl. In embodiments, when R5 is hydrogen R6 is not a substituted or unsubstituted C1-C4 alkyl. In embodiments, when R5 is hydrogen R6 is not a substituted Ci-C4 alkyl. In embodiments, when R5 is hydrogen R6 is not an unsubstituted Ci-C4 alkyl. In embodiments, when R5 is hydrogen R6 is not a substituted or unsubstituted Ci-C2 alkyl. In embodiments, when R5 is hydrogen R6 is not a substituted Ci-C4 alkyl. In embodiments, when R5 is hydrogen R6 is not an unsubstituted Ci-C4 alkyl. [0321] In embodiments, R6 is not hydrogen. In embodiments, R6 is not a substituted or unsubstituted Ci-C6 alkyl. In embodiments, R6 is not a substituted Ci-C6 alkyl. In embodiments, R6 is not an unsubstituted Ci-C6 alkyl. In embodiments, R6 is not a substituted or unsubstituted Ci-C4 alkyl. In embodiments, R6 is not a substituted Ci-C4 alkyl. In embodiments, R6 is not an unsubstituted Ci-C4 alkyl. In embodiments, R6 is not a substituted or unsubstituted Ci-C2 alkyl. In embodiments, R6 is not a substituted Ci-C4 alkyl. In embodiments, R6 is not an unsubstituted Ci-C4 alkyl.
[0322] In embodiments, R5 is not hydrogen. In embodiments, R5 is not a substituted or unsubstituted Ci-C6 alkyl. In embodiments, R5 is not a substituted Ci-C6 alkyl. In embodiments, R5 is not an unsubstituted Ci-C6 alkyl. In embodiments, R5 is not a substituted or unsubstituted Ci-C4 alkyl. In embodiments, R5 is not a substituted Ci-C4 alkyl. In embodiments, R5 is not an unsubstituted Ci-C4 alkyl. In embodiments, R5 is not a substituted or unsubstituted Ci-C2 alkyl. In embodiments, R5 is not a substituted Ci-C4 alkyl. In embodiments, R5 is not an unsubstituted Ci-C4 alkyl. [0323] In embodiments, when R5 is hydrogen R6 is not a 2 to 6 membered heteroalkyl. In embodiments, when R5 is hydrogen R6 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, when R5 is hydrogen R6 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, when R5 is hydrogen R6 is not a substituted 2 to 6 membered heteroalkyl. In
Figure imgf000111_0001
embodiments, when R is hydrogen R is not . In embodiments, when R is
Figure imgf000111_0002
hydrogen R6 is not ^ . In embodiments, when R5 is hydrogen R6 is not ^
O embodim nts, when R5 is hydrogen R6 is not ^ 0 . In embodiments, when R5
h drogen
Figure imgf000111_0003
In embodiments, when R is hydrogen R is not
Figure imgf000111_0004
[0324] In embodiments, when R5 is hydrogen R6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, when R5 is hydrogen R6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, when R5 is hydrogen R6 is not -C(0)-(substituted heteroalkyl). In
embodiments, when R5 is hydrogen R6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, when R5 is hydrogen R6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, when R5 is hydrogen R6 is not -C(0)-0-(substituted heteroalkyl).
[0325] In embodiments, R6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R6 is not -C(O)- (substituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(substituted heteroalkyl). In embodiments, R5 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R5 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R5 is not -C(0)-(substituted heteroalkyl). In embodiments, R5 is not -C(0)-0- (substituted or unsubstituted heteroalkyl). In embodiments, R5 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R5 is not -C(0)-0-(substituted heteroalkyl). [0326] In embodiments, R6 is not a 2 to 6 membered heteroalkyl. In embodiments, R6 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, R6 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R6 is not a substituted 2 to 6 membered heteroalkyl. In
O I O embodiments, R6 is not A O J< . In embodiments, R6 is not s *A ° / . In embodiments, R6
O O
A ^ . In embodiments, R6 is not A ^ . In embodiments, R° is not
Figure imgf000112_0001
In embodiments, R6 is not
[0327] In embodiments, R5 is not a 2 to 6 membered heteroalkyl. In embodiments, R5 is not a substituted 2 to 6 membered heteroalkyl. In embodiments, R5 is not an unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R5 is not a substituted 2 to 6 membered heteroalkyl. In
embodiments, R5 is not
Figure imgf000112_0002
. In embodiments, R5
is not
Figure imgf000112_0003
In embodiments, R5 is not . In embodiments, R1 is not N02.
In embodiments, R1 3 is not N02.
[0328] In embodiments, the compound does not have the formula:
Figure imgf000112_0004
wherein R1, zl, L1, R2, z2, Y, L2, R4,
L3, and L4 are as described herein.
[0329] In embodiments, the compound does not have the formula:
Figure imgf000113_0001
wherein R1, zl, L1, R2, z2, Y,
L2, R4, and R6 are as described herein. In embodiments, the compound does not have the formula:
Figure imgf000113_0002
, wherein R1, zl, L1, L2, R4, and R6 are as described herein. In embodiments, the compound does not have the formula:
Figure imgf000113_0003
, wherein R1, zl, L1, L2, R4, and R6 are as described herein. In embodiments, the compound does not have the formula:
Figure imgf000113_0004
, wherein R1, zl, L1, L2, R4, and R6 are as described herein. In embodiments, the compound does not have the formula:
Figure imgf000113_0005
, wherein R1, zl, L1, L2, R4, and R22 are as described herein. In embodiments, R6 is not hydrogen. In embodiments, R6 is not a substituted or unsubstituted Ci-C6 alkyl. In embodiments, R6 is not a substituted Ci-C6 alkyl. In embodiments, R6 is not an unsubstituted Ci-C6 alkyl. In embodiments, R6 is not a substituted or unsubstituted C1-C4 alkyl. In embodiments, R6 is not a substituted C1-C4 alkyl. In embodiments, R6 is not an unsubstituted C1-C4 alkyl. In embodiments, R6 is not a substituted or unsubstituted Ci-C2 alkyl. In embodiments, R6 is not a substituted C1-C4 alkyl. In embodiments, R6 is not an unsubstituted C1-C4 alkyl. In embodiments, R6 is not -C(0)-(substituted or unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-(unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-(substituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(substituted or unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(unsubstituted heteroalkyl). In embodiments, R6 is not -C(0)-0-(substituted heteroalkyl). In embodiments, R6 is not hydrogen.
[0330] In embodiments, R6 is not a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R6 is not substituted or unsubstituted cycloalkyl. R6 is not substituted or
unsubstituted C3-C8 cycloalkyl. R6 is not substituted cycloalkyl. R6 is not substituted C3-C8 cycloalkyl. R6 is not unsubstituted cycloalkyl. R6 is not unsubstituted C3-C8 cycloalkyl.
[0331] R6 is not substituted or unsubstituted 3 to 8 membered heterocycloalkyl. R6 is not a substituted or unsubstituted 4 to 6 membered heterocycloalkyl. R6 is not a substituted or unsubstituted 5 or 6 membered heterocycloalkyl. R6 is not substituted or unsubstituted 5 membered heterocycloalkyl. R6 is not substituted or unsubstituted 6 membered heterocycloalkyl. In embodiments, R6 is not a substituted or unsubstituted heterocycloalkyl (e.g., substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or
unsubstituted oxazolidinyl, substituted or unsubstituted thiazolidinyl, substituted or unsubstituted dioxolanyl, substituted or unsubstituted dithiolanyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted dithianyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted azepinyl, substituted or unsubstituted oxiranyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl.
[0332] In embodiments, R6 is not a substituted or unsubstituted C6-Ci2 aryl. In embodiments, R6 is not a substituted C6-Ci2 aryl. In embodiments, R6 is an unsubstituted C6-Ci2 aryl. In embodiments, R6 is not a substituted or unsubstituted C6-Ci0 aryl. In embodiments, R6 is not a substituted C6-Cio aryl. In embodiments, R6 is an unsubstituted C6-Cio aryl. In embodiments, R6 is an unsubstituted phenyl. In embodiments, R6 is not a substituted phenyl. In embodiments, R6 is an unsubstituted naphthyl. In embodiments, R6 is not a substituted naphthyl. In embodiments, R6 is an unsubstituted biphenyl. In embodiments, R6 is not a substituted biphenyl.
[0333] In embodiments, R6 is not a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, R6 is not a substituted 5 to 10 membered heteroaryl. In embodiments, R6 is an unsubstituted 5 to 10 membered heteroaryl. In embodiments, R6 is not a substituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments, R6 is not a substituted 5 to 6 membered heteroaryl. In embodiments, R6 is an unsubstituted 5 to 6 membered heteroaryl. In embodiments, R6 is not a substituted or unsubstituted 5 membered heteroaryl. In embodiments, R6 is not a substituted 5 membered heteroaryl. In embodiments, R6 is an unsubstituted 5 membered heteroaryl. In embodiments, R6 is not a substituted or unsubstituted 6 membered heteroaryl. In embodiments, R6 is not a substituted 6 membered heteroaryl. In embodiments, R6 is an unsubstituted 6 membered heteroaryl.
[0334] In embodiments, R6 is not unsubstituted triazolyl. In embodiments, R6 is not substituted triazolyl. In embodiments, R6 is not unsubstituted tetrazolyl. In embodiments, R6 is not substituted tetrazolyl. In embodiments, R6 is not substituted or unsubstituted pyridyl. R6 is not substituted or unsubstituted heteroaryl. R6 is not a substituted or unsubstituted heteroaryl such as, for example, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyranyl, substituted or unsubstituted thiopyranyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimindyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted oxazinyl, substituted or unsubstituted thiazinyl, substituted or unsubstituted doxinyl, substituted or unsubstituted dithiinyl, substituted or unsubstituted azetyl, substituted or unsubstituted oxetyl, substituted or unsubstituted thietyl, substituted or unsubstituted azirinyl, substituted or unsubstituted oxirenyl or substituted or unsubstituted thienyl. R6 is not substituted or
unsubstituted pyridinyl.
III. Pharmaceutical compositions
[0335] In an aspect is provided a pharmaceutical composition including a compound described herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0336] In embodiments of the pharmaceutical compositions, the compound, or
pharmaceutically acceptable salt thereof, is included in a therapeutically effective amount.
[0337] In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the second agent is an agent for treating asthma. In embodiments of the pharmaceutical
compositions, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-inflammatory agent. In embodiments, the second agent is an anti-autoimmune disease agent.
IV. Methods of use
[0338] In an aspect is provided a method for treating asthma, the method including
administering to a subject in need thereof an effective amount of a compound as described herein.
[0339] Provided herein are methods for treating asthma. In embodiments, the asthma is severe asthma. In embodiments, the asthma is acute severe asthma. In embodiments, the asthma is moderate asthma. In one aspect, is a method for treating asthma by administering to a subject in need thereof an α5β1 -inhibitor (e.g., where the α5β1 -inhibitor is a compound having a formulae described herein, including embodiments thereof). In an embodiment, is a method for treating asthma by administering to a subject in need thereof a therapeutically effective amount of an α5β1 -inhibitor, where the α5β1 -inhibitor is an α5β1 -inhibitor compound having the formulae described herein, including embodiments thereof. The α5β1 -inhibitor compound may be a compound having a formula described herein, including embodiments thereof. The α5β1- inhibitor compound may be a pharmaceutical composition as described herein, including embodiments thereof. In embodiments, the compound is ΗΠ-1094, HIJ-1099, HIJ-1204, ΗΠ- 1437, HIJ-1483, or HIJ-1491.
[0340] In an aspect is provided a method of treating cancer including administering to a subject in need thereof an effective amount of a compound described herein. In embodiments, the cancer is ovarian cancer, bladder cancer, head and neck cancer, brain cancer, breast cancer, lung cancer, cervical cancer, liver cancer, colorectal cancer, pancreatic cancer, glioblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma, renal cancer, renal cell carcinoma, non-small cell lung cancer, uterine cancer, testicular cancer, anal cancer, bile duct cancer, biliary tract cancer, gastrointestinal carcinoid tumors, esophageal cancer, gall bladder cancer, appendix cancer, small intestine cancer, stomach (gastric) cancer, urinary bladder cancer, genitourinary tract cancer, endometrial cancer, nasopharyngeal cancer, head and neck squamous cell carcinoma, or prostate cancer. In embodiments, the cancer is ovarian cancer, bladder cancer, head and neck cancer, prostate cancer, brain cancer, breast cancer, lung cancer, cervical cancer, liver cancer, bone cancer, or spinal cancer.
[0341] In an aspect is provided a method of treating an inflammatory disease including administering to a subject in need thereof an effective amount of a compound described herein. [0342] In embodiments, the inflammatory disease is arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis.
[0343] In an aspect is provided a method of treating an autoimmune disease including administering to a subject in need thereof an effective amount of a compound described herein.
[0344] In embodiments, the autoimmune disease is arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, or atopic dermatitis.
[0345] In an aspect is provided a method of detecting the presence of α5β1 integrin or inhibiting α5β1 integrin activity, the method including contacting an α5β1 integrin with a compound as described herein.
[0346] In embodiments, the method includes administering a second agent (e.g. therapeutic agent). In embodiments, the method includes administering a second agent (e.g. therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an anti-inflammatory agent. [0347] In embodiments, the method includes detecting the presence of α5β1 integrin and inhibiting α5β1 integrin activity. In embodiments, the method includes detecting the presence of α5β1 integrin. In embodiments, the method includes inhibiting α5β1 integrin activity.
[0348] Further provided herein are methods of detecting α5β1 expression in a cell. In one aspect is a method of detecting α5β1 expression in a cell by contacting a cell with an α5β1- specific moiety (e.g., compound described herein) and allowing the o^l-specific moiety to bind to the cell. The o^l-specific moiety is detected, thereby detecting α5β1 expression in a cell. The detection may be performed using techniques known in the art (e.g. fluorescence detection or radiolabel detection). The cell may form part of an organism (e.g. a human). [0349] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. IV. EMBODIMENTS
[0350] Embodiments contemplated herein include embodiments PI to PI 11 following.
[0351] Embodiment PI . A compound having the formula:
Figure imgf000118_0001
wherein, R1 is independently halogen,
Figure imgf000118_0002
-SCvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)ORlc, - R1AORlc, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX23, -OCH2X2, -OCHX2 2, -CN, -SO^R20, -SOv2 R2AR2B, - HC(0) R2AR2B, -N(0)m2, -NR2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C, -NK2A
2C 2 A 2C
C(0)OR , -NR OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently hydrogen, -CX4 3, -CN, -COOH,
-CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is unsubstituted alkyl ene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0-, -S(O) -, -S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted aryl ene, substituted or unsubstituted
heteroarylene; R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or
substituted or unsubstituted heteroalkyl; R5 and R6 are independently hydrogen,
Figure imgf000119_0001
Figure imgf000119_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, - CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, - CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, - HNH2, -O H2, - NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, Χ 1, Χ 2, Χ 4, Χ 7, Χ 8, Χ 9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 4; and ml, m2, vl and v2 are independently 1 or 2; zl is an integer from 0 to 5; z2 is an integer from 0 to 9; with the proviso that when R5 is hydrogen R6 is not hydrogen.
[0352] Embodiment P2. The compound of embodiment PI, wherein zl is an integer from 1 to
5.
[0353] Embodiment P3. The compound of embodiments PI or P2, wherein Y is -C-C-, -C=C-, -0-C-, -C-0-, -C-0-C-,-C-S-, -S-C, or -C-S-C-.
[0354] Embodiment P4. The compound of any one of embodiments PI to P3, wherein
Figure imgf000120_0001
[0355] Embodiment P5. The compound of any one of embodiments PI to P3 having the
formula:
Figure imgf000120_0002
[0356] Embodiment P6. The compound of any one of embodiments PI to P5, wherein L1 is a bond.
[0357] Embodiment P7. The compound of any one of embodiments PI to P6, wherein R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH, - CO H2, -SH, -SO2, -S02CH3 -S03H, -OS03H, -S02NH2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
[0358] Embodiment P8. The compound of any one of embodiments PI to P6, wherein R1 is independently halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci- C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0359] Embodiment P9. The compound of any of embodiments PI to P8, wherein L2 is unsubstituted Ci-C2 alkylene.
[0360] Embodiment P10. The compound of any of embodiments PI to P8, wherein L2 is unsubstituted methylene.
[0361] Embodiment PI 1. The compound of any of embodiments PI to P10, wherein R4 is hydrogen.
[0362] Embodiment P12. The compound of any one of embodiments PI to PI 1, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0363] Embodiment P13. The compound of any one of embodiments PI to PI 1, wherein L3 is a bond. [0364] Embodiment P14. The compound of any one of embodiments PI to PI 1, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0365] Embodiment P15. The compound of any one of embodiments PI to PI 1, wherein L3 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0366] Embodiment P16. The compound of any one of embodiments PI to PI 1, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0367] Embodiment PI 7. The compound of any one of embodiments 1 to 11, wherein L3 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
[0368] Embodiment P18. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0369] Embodiment P19. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0370] Embodiment P20. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0371] Embodiment P21. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene. [0372] Embodiment P22. The compound of any one of embodiments PI to P17, wherein L4 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0373] Embodiment P23. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
[0374] Embodiment P24. The compound of any one of embodiments PI to P17, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0375] Embodiment P25. The compound of any one of embodiments PI to P17, wherein L4 is unsubstituted phenylene. 5
[0376] Embodiment P26. The compound of any one of embodimentsP 1 to P25, wherein R
and R are independently hydrogen,
Figure imgf000123_0001
, or substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
5
[0377] Embodiment P27. The compound of any one of embodiments PI to P25, wherein R
and R6 are independently hydrogen,
Figure imgf000123_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0378] Embodiment P28. The compound of any one of embodiments PI to P25, wherein R5 substituted or unsubstituted 5 to 6 membered heteroaryl.
[0379] Embodiment P29. The compound of any one of embodiments PI to P25, wherein R6 substituted or unsubstituted 5 to 6 membered heteroaryl.
[0380] Embodiment P30. The compound of any one of embodiments PI to P25, wherein R
and R6 are independently hydrogen,
Figure imgf000123_0003
[0381] Embodiment P31. The compound of any one of embodiments PI to P25, wherein R5 is
NH NH NR10 NNFR1 0
¾^NH2 ¾^ NHR9 ¾ NHR9 * NH,
hydrogen and R6 is , u , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0382] Embodiment P32. The compound of any one of embodiments PI to P25, wherein R5
NH NH NR10 NR1 0
t¾^NH2 t¾^ NHR9 ¾ NHR9 ¾ NH2
hydrogen and R6 is , u , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0383] Embodiment P33. The compound of any one of embodiments PI to P25, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0384] Embodiment P34. The compound of any one of embodiments PI to P25, wherein R5 is
hydrogen and R6 is
Figure imgf000124_0001
[0385] Embodiment P35. The compound of any one of embodiments PI to P25, wherein R5 is
hydrogen and
Figure imgf000124_0002
[0386] Embodiment P36. The compound of any one of embodiments PI to P25, wherein R is hydrogen and R6 is substituted or unsubstituted heteroaryl.
[0387] Embodiment P37. The compound of any one of embodiments PI to P25, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0388] Embodiment P38. The compound of any one of embodiments PI to P37, wherein R3 is hydrogen.
[0389] Embodiment P39. The compound of any one of embodiments PI to P37, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0390] Embodiment P40. The compound of embodiment PI, having the formula:
Figure imgf000124_0003
Figure imgf000125_0001
 [0392] Embodiment P42. The compound of embodiment PI, having the formula:
Figure imgf000126_0001
[0393] Embodiment P43. The compound of embodiment PI, having the formula: f embodiment PI, having the formula:
Figure imgf000126_0002
of embodiment PI, having the formula:
Figure imgf000126_0003
of embodiment PI, having the formula:
Figure imgf000126_0004
of embodiment PI, having the formula:
Figure imgf000126_0005
[0398] Embodiment P48. The compound of embodiments PI, having the formula:
Figure imgf000126_0006
0399] Embodiment P49. The compound of embodiment PI, having the formula:
Figure imgf000127_0001
[0400] Embodiment P50. The compound of embodiment PI, having the formula:
Figure imgf000127_0002
[0401] Embodiment P51. The compound of embodiment PI, having the formula:
Figure imgf000127_0003
[0402] Embodiment P52. The compound of embodiment PI, having the formula:
Figure imgf000127_0004
[0403] Embodiment P53. The compound of embodiment PI, having the formula:
Figure imgf000127_0005
[0404] Embodiment P54. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of embodiments PI to P53.
[0405] Embodiment P55. A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:
Figure imgf000128_0001
R is independently halogen,
Figure imgf000128_0002
-CN, -SO„iR1D,
-SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mb - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0R1C, - R1A0R1C, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, - C- O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX2 2, -CN, -SO„2R2D, -SOv2NR2AR2B, -NHC(0)NR2AR2B, -N(0)m2, -NR2AR2B, -C( 0)R2C, -C(0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C, -NR2AC(0)OR2C, -N R OR , -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is unsubstituted alkylene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, - S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R8 is
hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted
NH NH NR10 t^ NH2 ¾^ NHR9 ' NHRS heteroalkyl; R5 and R6 are independently hydrogen,
Figure imgf000129_0001
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, - COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, - NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -N3, - CX10 3, -CHX102, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, - S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC (0)NHNH2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or
1 2 4 7 8 9 10
substituted or unsubstituted heteroaryl; each X, Χ , Χ , Χ , Χ , Χ , Χ , and X are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 4; ml, m2, vl and v2 are independently 1 or 2; zl is an integer from 0 to 5; and z2 is an integer from 0 to 9. [0406] Embodiment P56. The method of embodiment P55, wherein zl is an integer from 1 to
5.
[0407] Embodiment P57. The method of any one of embodiments P55 or P56, wherein Y is - C-C-, -C=C-, -0-C-, -C-0-, -C-0-C-,-C-S-, -S-C, or -C-S-C-. [0408] Embodiment P58. The method of any one of embodiments P55 to P57, wherein
Figure imgf000130_0001
[0409] Embodiment P59. The method of an one of embodiments P55 to P57 having the
formula
Figure imgf000130_0002
[0410] Embodiment P60. The method of any one of embodiments P55 to P59, wherein L1 is a bond.
[0411] Embodiment P61. The method of any one of embodiments P55 to P60, wherein R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH, - CO H2, -SH, -SO2, -S02CH3 -S03H, -OS03H, -S02NH2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
[0412] Embodiment P62. The method of any one of embodiments P55 to P60, wherein R1 is independently halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci- C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0413] Embodiment P63. The method of any of embodiments P55 to P62, wherein L2 is unsubstituted C1-C2 alkylene.
[0414] Embodiment P64. The method of any of embodiments P55 to P62, wherein L2 is unsubstituted methylene. [0415] Embodiment P65. The method of any of embodiments P55 to P64, wherein R4 is hydrogen.
[0416] Embodiment P66. The method of any one of embodiments P55 to P65, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0417] Embodiment P67. The method of any one of embodiments P55 to P65, wherein L3 is a bond.
[0418] Embodiment P68. The method of any one of embodiments P55 to P65, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0419] Embodiment P69. The method of any one of embodiments P55 to P65, wherein L3 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0420] Embodiment P70. The method of any one of embodiments P55 to P65, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0421] Embodiment P71. The method of any one of embodiments P55 to P65, wherein L3 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0422] Embodiment P72. The method of any one of embodiments P55 to P71, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0423] Embodiment P73. The method of any one of embodiments P55 to P71, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. [0424] Embodiment P74. The method of any one of embodiments P55 to P71, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0425] Embodiment P75. The method of any one of embodiments P55 to P70, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0426] Embodiment P76. The method of any one of embodiments P55 to P71, wherein L4 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0427] Embodiment P77. The method of any one of embodiments P55 to P71, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. [0428] Embodiment P78. The method of any one of embodiments P55 to 7P1, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene.
[0429] Embodiment P79. The method of any one of embodiments P55 to P71, wherein L4 is unsubstituted phenylene. [0430] Embodiment P 80. The method of any one of embodiments P55 to P79, wherein R
and R6 are independently hydrogen,
Figure imgf000132_0001
, or substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0431] Embodiment P81. The method of any one of embodiments P55 to P79, wherein R5 and
R6 are independently hydrogen,
Figure imgf000132_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0432] Embodiment P82. The method of any one of embodiments P55 to P79, wherein R5 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0433] Embodiment P83. The method of any one of embodiments P55 to P79, wherein R6 is substituted or unsubstituted 5 to 6 membered heteroaryl. [0434] Embodiment P84. The method of any one of embodiments P55 to P79, wherein R5 and
R6 are independently hydrogen,
Figure imgf000133_0001
, or
[0435] Embodiment P85. The method of any one of embodiments P55 to P79, wherein R5 is
NH NH NR10 NR1 0
¾^NH2 <¾^ NHR9 ¾ NHR9 '¾ NH2
hydrogen and R6 is α , u °* , ^ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0436] Embodiment P86. The method of any one of embodiments 5P5 to P79, wherein R5 is
NH NH NR10 NR1 0
¾^NH2 t¾^ NHR9 \ NHR9 *¾ ΝΗ2
hydrogen and R6 is *~ , *~ , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0437] Embodiment P87. The method of any one of embodiments P55 to P79, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0438] Embodiment P88. The method of any one of embodiments P55 to P79, wherein R5 is
hydrogen and R6 is
Figure imgf000133_0002
[0439] Embodiment P89. The method of any one of embodiments P55 to P79, wherein R is
hydrogen and R6 is
Figure imgf000133_0003
[0440] Embodiment P90. The method of any one of embodiments P55 to P79, wherein R5 is hydrogen and R6 is substituted or unsubstituted heteroaryl.
[0441] Embodiment P91. The method of any one of embodiments P55 to P79, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl. [0442] Embodiment P92. The method of any one of embodiments P55 to P91, wherein R3 is hydrogen.
[0443] Embodiment P93. The method of any one of embodiments P55 toP 91, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
0444] Embodiment P94. The method of embodiment P55, having the formula:
Figure imgf000134_0001
Figure imgf000135_0001
Embodiment P95. The method of embodiment P55, having the formula:
Figure imgf000135_0002
[0446] Embodiment P96. The method of embodiment P55, having the formula:
Figure imgf000135_0003
[0447] Embodiment P97. The method of embodiment P55, having the formula:
Figure imgf000135_0004
[0448] Embodiment P98. The method of embodiment P55, having the formula:
Figure imgf000135_0005
embodiment P55, having the formula:
Figure imgf000136_0001
[0450] Embodiment P100. The method of embodiment P55, having the formula:
Figure imgf000136_0002
of embodiment P55, having the formula:
Figure imgf000136_0003
[0452] Embodiment P102. The method of embodiment P55, having the formula:
Figure imgf000136_0004
[0453] Embodiment P103. The method of embodiment P55, having the formula:
Figure imgf000136_0005
odiment P104. The method of embodiment P55, having the formula: cAoHH °
Figure imgf000136_0006
[0455] Embodiment P105. The method of embodiment P55, having the formula:
Figure imgf000136_0007
[0456] Embodiment P106. The method of embodiment P55, having the formula:
Figure imgf000137_0001
[0457] Embodiment P107. The method of embodiment P55, having the formula:
Figure imgf000137_0002
[0458] Embodiment PI 08. A method of detecting the presence of α5β 1 integrin or inhibiting α5β 1 integrin activity, said method comprising contacting an α5β1 integrin with a compound having the formula: A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt
thereof, having the formula:
Figure imgf000137_0003
wherein, R1 is independently halogen,
Figure imgf000137_0004
-CN, -SO„iR1D, -SCvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)ORlc, - R1AORlc, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -O- C-, -C-0-, - C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, - CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SO^R20, -SOv2NR2AR2B,
-NHC(0) R2AR2B, -N(0)m2, - R2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS 02R2D, - R2AC(0)R2C, - R2AC(0)OR2C, - R2AOR2C, -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently
hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is unsubstituted alkyl ene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L4 is -0-, -S-, -N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or
unsubstituted heteroarylene; R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R5 and R6 are independently hydrogen,
NH NH NR10 NR10
l¾^ NH2 ¾^ NHR9 ¾^ NHR9 NH2
*~ ~ , , α , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted
heterocycloalkyl or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -SO4H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; RiU is hydrogen, halogen, -N3, -CX 3, -CHX 2, -CH2X , -CN, -CHO, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, - HNH2, -O H2, -NHC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, Χ 1, Χ 2, Χ 4, Χ 7, Χ 8, Χ 9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 4; ml, m2, vl and v2 are independently 1 or 2; zl is an integer from 0 to 5; and z2 is an integer from 0 to 9.
[0459] Embodiment PI 09. The method of embodiment PI 08, wherein said method comprises detecting the presence of α5β1 integrin and inhibiting α5β1 integrin activity.
[0460] Embodiment PI 10. The method of embodiment PI 08, wherein said method comprises detecting the presence of α5β1 integrin.
[0461] Embodiment Pi l l . The method of embodiment PI 08, wherein said method comprises inhibiting α5β1 integrin activity.
IV. ADDITIONAL EMBODIMENTS
[0462] Embodiment 1. A compound having the formula:
Figure imgf000139_0001
; wherein, R is independently halogen, -N3, -CX , -CHX^, -CT^X1, -OCX 3,
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOviNR1AR1B, -OSOviR1D, -NHC(0)NR1AR1B,
-N(0)mb -NR1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0)NR1AR1B, -OR1D, -NR1AS02R1D, -NR1AC(0)R1C, - R1AC(0)ORlc, - R1A0R1C, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-; R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX22, -CN, -SO^R20, -SOv2 R2AR2B, - HC(0) R2AR2B, -N(0)m2, - R2AR2B, -C( 0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C,
-NR2AC(0)OR2C, - R2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently
hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is unsubstituted alkylene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L4 is -0-, -S- - N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene; R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R5 and R6 are independently hydrogen,
Figure imgf000141_0001
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, - CN, -CHO, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, -NHNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, - CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, - NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, Χ 1, Χ 2, Χ 4, Χ 7, Χ 8, Χ 9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 3; ml, m2, vl and v2 are independently 1 or 2; zl is an integer from 0 to 5; z2 is an integer from 0 to 9; and z3 is 0 or 1; with the proviso that when R5 is hydrogen R6 is not hydrogen.
[0463] Embodiment 2. The compound according to embodiment 1 having the formula:
Figure imgf000142_0001
R1 is independently halogen,
Figure imgf000142_0002
-CH2X1, -OCX13, -
OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C( 0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D, - R1AC(0)R1C, - R1AC(0)0R1C, -N R1A0R1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary^L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -O- C-, -C-0-,
-C-O-C, -S-C-, -C-S-,or -C-S-C-;R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2,
-OCHX2 2, -CN, -SO„2R2D, -SOv2NR2AR2B, -NHC(0)NR2AR2B, -N(0)m2, -NR2AR2B, -C(0)R2C, -C (0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C, -NR2AC(0)OR2C,
-NR OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety;R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2,
-CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;L2 is unsubstituted alkylene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;L4 is -0-, -S-, -N(R8)-, -C(O)-, C(0)0-, -S(O) -, - S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;R8 is
hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted
heteroalkyl;R5 and R6 are independently hydrogen,
Figure imgf000143_0001
NR10
NH2
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH,
-NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ;R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH,
-NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 4; ml, m2, vl and v2 are independently 1 or 2;zl is an integer from 0 to 5; and z2 is an integer from 0 to 9; with the proviso that when R5 is hydrogen R6 is not hydrogen.
[0464] Embodiment 3. The compound of embodiment 1, wherein zl is an integer from 1 to 5.
[0465] Embodiment 4. The compound of embodiment 1, wherein zl is 0.
[0466] Embodiment 5. The compound of any one of embodiments 1 to 3, wherein Y is -C- C-, -C=C-, -0-C-, -C-0-, -C-0-C-,-C-S-, -S-C, or -C-S-C-.
[0467] Embodiment 6. The compound of any one of embodiments 1 to 5, wherein
Figure imgf000144_0001
has the formula:
[0468] Embodiment 7. The compound of any one of embodiments 1 to 5 having formula:
Figure imgf000144_0002
[0469] Embodiment 8. The compound of any one of embodiments 1 to 7, wherein L1 is a bond.
[0470] Embodiment 9. The compound of any one of embodiments 1 to 8, wherein R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH,
-CO H2, -SH, -SO2, -S02CH3 -S03H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
[0471] Embodiment 10. The compound of any one of embodiments 1 to 8, wherein R1 is independently halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci-
C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0472] Embodiment 11. The compound of any of embodiments 1 to 10, wherein L2 is unsubstituted C1-C2 alkylene.
[0473] Embodiment 12. The compound of any of embodiments 1 to 10, wherein L2 is unsubstituted methylene. [0474] Embodiment 13. The compound of any of embodiments 1 to 12, wherein R4 is hydrogen.
[0475] Embodiment 14. The compound of any one of embodiments 1 to 13, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkyl ene, substituted or unsubstituted phenyl ene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0476] Embodiment 15. The compound of any one of embodiments 1 to 13, wherein L3 is a bond.
[0477] Embodiment 16. The compound of any one of embodiments 1 to 13, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0478] Embodiment 17. The compound of any one of embodiments 1 to 13, wherein L3 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0479] Embodiment 18. The compound of any one of embodiments 1 to 13, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0480] Embodiment 19. The compound of any one of embodiments 1 to 13, wherein L3 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0481] Embodiment 20. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0482] Embodiment 21. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0483] Embodiment 22. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0484] Embodiment 23. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0485] Embodiment 24. The compound of any one of embodiments 1 to 19, wherein L4 is an oxo-substituted Ci-C8 alkylene, or oxo-substituted 2 to 8 membered heteroalkylene.
[0486] Embodiment 25. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
[0487] Embodiment 26. The compound of any one of embodiments 1 to 19, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0488] Embodiment 27. The compound of any one of embodiments 1 to 19, wherein L4 is unsubstituted phenylene .
[0489] Embodiment 28. The compound of any one of embodiments 1 to 27, wherein R5 and
R6 are independently hydrogen,
Figure imgf000146_0001
, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0490] Embodiment 29. The compound of any one of embodiments 1 to 27, wherein R5 and
R6 are independently hydrogen,
Figure imgf000146_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0491] Embodiment 30. The compound of any one of embodiments 1 to 27, wherein R5 is substituted or unsubstituted 5 to 6 membered heteroaryl. [0492] Embodiment 31. The compound of any one of embodiments 1 to 27, wherein R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0493] Embodiment 32. The compound of any one of embodiments 1 to 27, wherein R5 and
R6 are independently hydrogen,
Figure imgf000147_0001
[0494] Embodiment 33. The compound of any one of embodiments 1 to 27, wherein R5 is
hydrogen and R6 is
Figure imgf000147_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0495] Embodiment 34. The compound of any one of embodiments 1 to 27, wherein R5
hydrogen and R6 is
Figure imgf000147_0003
, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0496] Embodiment 35. The compound of any one of embodiments 1 to 27, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0497] Embodiment 36. The compound of any one of embodiments 1 to 27, wherein R5 is
hydrogen and R6 is
Figure imgf000147_0004
[0498] Embodiment 37. The compound of any one of embodiments 1 to 27, wherein R5 is
hydrogen and R6
Figure imgf000147_0005
[0499] Embodiment 38. The compound of any one of embodiments 1 to 27, wherein R5 is hydrogen and R6 is substituted or unsubstituted heteroaryl. [0500] Embodiment 39. The compound of any one of embodiments 1 to 27, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0501] Embodiment 40. The compound of any one of embodiments 1 to 39, wherein R3 is hydrogen.
[0502] Embodiment 41. The compound of any one of embodiments 1 to 39, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0503] Embodiment 42. The compound of embodiment 1, having the formula:
Figure imgf000148_0001
Figure imgf000149_0001

Figure imgf000150_0001
[0506] Embodiment 45. The compound of embodiment 1, having the formula:
Figure imgf000150_0002
[0507] Embodiment 46. The compound of embodiment 1, having the formula:
Figure imgf000150_0003
[0508] 47. The compound of embodiment 1, having the formula:
Figure imgf000150_0004
[0509] Embodiment 48. The compound of embodiment 1, having the formula:
Figure imgf000150_0005
[0510] Embodiment 49. The compound of embodiment 1, having the formula:
Figure imgf000150_0006
[0511] Embodiment 50. The compound of embodiment 1, having the formula:
Figure imgf000150_0007
[0512] Embodiment 51. The compound of embodiment 1, having the formula:
Figure imgf000151_0001
[0513] Embodiment 52. The compound of embodiment 1, having the formula:
Figure imgf000151_0002
[0514] Embodiment 53. The compound of embodiment 1, having the formula:
Figure imgf000151_0003
[0515] Embodiment 54. The compound of embodiment 1, having the formula:
Figure imgf000151_0004
[0516] Embodiment 55. The compound of embodiment 1, having the formula:
Figure imgf000151_0005
[0517] Embodiment 56. The compound of embodiment 1, having the formula:
Figure imgf000152_0001
[0518] Embodiment 57. The compound of embodiment 1, having the formula:
Figure imgf000152_0002
[0519] Embodiment 58. The compound of embodiment 1, having the formula:
Figure imgf000152_0003
[0520] Embodiment 59. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of embodiments 1 to 55.
[0521] Embodiment 60. A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound, or a harmaceuticall acceptable salt thereof, having the formula:
Figure imgf000152_0004
wherein, R1 is independently halogen, -N3,
Figure imgf000152_0005
-OCXl 3,
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, -OSOviR1D, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D,
Figure imgf000152_0006
-O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted
heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-;R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3,
OCH2X2, -OCHX22, -CN, -SO„2R2D, -SOv2 R2AR2B, - HC(0) R2AR2B, -N(0)m2, - R2AR2B, -C( 0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C, - R2AC(0)OR2C, -N R OR , -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety;R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2,
-CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;L2 is unsubstituted alkylene; L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, - S(0)2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;R8 is
hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted
heteroalkyl ;R5 and R6 are independently hydrogen,
Figure imgf000153_0001
NR10
NH2
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH,
-NH2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, - HNH2, -ONH2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ;R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH,
-NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are
independently an integer from 0 to 3; ml, m2, vl and v2 are independently 1 or 2;zl is an integer from 0 to 5; z2 is an integer from 0 to 9; and z3 is 0 or 1.
[0522] Embodiment 61. The method of embodiment 60, wherein zl is an integer from 1 to 5.
[0523] Embodiment 62. The method of one of embodiments 60 or 61, wherein Y is -C-C-, - C=C-, -0-C-, -C-0-, -C-0-C-,-C-S-, -S-C, or -C-S-C-. [0524] Embodiment 63. The method of any one of embodiments 60 to 62, wherein
Figure imgf000155_0001
has the formula:
[0525] Embodiment 64. The method of any one of embodiments 60 to 62 having the formula:
Figure imgf000155_0002
[0526] Embodiment 65. The method of any one of embodiments 60 to 64, wherein L1 is a bond.
[0527] Embodiment 66. The method of any one of embodiments 60 to 65, wherein R1 is independently halogen, -N3, -CF3, -CC13, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH, - CO H2, -SH, -SO2, -S02CH3 -S03H, -OS03H, -S02NH2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
[0528] Embodiment 67. The method of any one of embodiments 60 to 65, wherein R1 is independently halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted C C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0529] Embodiment 68. The method of any of embodiments 60 to 67, wherein L2 is unsubstituted Ci-C2 alkyl ene.
[0530] Embodiment 69. The method of any of embodiments 60 to 67, wherein L2 is unsubstituted methylene. [0531] Embodiment 70. The method of any of embodiments 60 to 69, wherein R4 is hydrogen.
[0532] Embodiment 71. The method of any one of embodiments 60 to 70, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0533] Embodiment 72. The method of any one of embodiments 60 to 70, wherein L3 is a bond. [0534] 73. The method of any one of embodiments 60 to 70, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0535] Embodiment 74. The method of any one of embodiments 60 to 70, wherein L3 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene. [0536] Embodiment 75. The method of any one of embodiments 60 to 70, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0537] Embodiment 76. The method of any one of embodiments 60 to 70, wherein L3 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
[0538] Embodiment 77. The method of any one of embodiments 60 to 76, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0539] Embodiment 78. The method of any one of embodiments 60 to 76, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
[0540] Embodiment 79. The method of any one of embodiments 60 to 76, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene.
[0541] Embodiment 80. The method of any one of embodiments 60 to 75, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene. [0542] Embodiment 81. The method of any one of embodiments 60 to 76, wherein L4 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene.
[0543] Embodiment 82. The method of any one of embodiments 60 to 76, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
[0544] Embodiment 83. The method of any one of embodiments 60 to 76, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.
[0545] Embodiment 84. The method of any one of embodiments 60 to 76, wherein L4 is unsubstituted phenylene.
[0546] Embodiment 85. The method of any one of embodiments 60 to 84, wherein R5 and
NR10
¾^NHR9
R6 are independently hydrogen, , or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0547] Embodiment 86. The method of any one of embodiments 60 to 84, wherein R5 and
R6 are independently hydrogen,
Figure imgf000157_0001
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
[0548] Embodiment 87. The method of any one of embodiments 60 to 84, wherein R5 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0549] Embodiment 88. The method of any one of embodiments 60 to 84, wherein R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0550] Embodiment 89. The method of any one of embodiments 60 to 84, wherein R5 and
R6 are independently hydrogen,
Figure imgf000157_0002
, or
[0551] Embodiment 90. The method of any one of embodiments 60 to 84, wherein R5 is
hydrogen and R6 is
Figure imgf000157_0003
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0552] Embodiment 91. The method of any one of embodiments 60 to 84, wherein R5 is
NH NH NR 0 NR10
t¾^NH2 t¾^NHR9 ¾^NHR9 '¾^NH2
hydrogen and R6 is °- , α *~ *~ , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0553] Embodiment 92. The method of any one of embodiments 60 to 84, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
[0554] Embodiment 93. The method of any one of embodiments 60 to 84, wherein R5 is
hydrogen and R6 is
Figure imgf000158_0001
[0555] Embodiment 94. The method of any one of embodiments 60 to 84, wherein R5 is
hydrogen and
Figure imgf000158_0002
[0556] Embodiment 95. The method of any one of embodiments 60 to 84, wherein R is hydrogen and R6 is substituted or unsubstituted heteroaryl.
[0557] Embodiment 96. The method of any one of embodiments 60 to 84, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
[0558] Embodiment 97. The method of any one of embodiments 60 to 96, wherein R3 is hydrogen.
[0559] Embodiment 98. The method of any one of embodiments 60 to 96, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 0560] Embodiment 99. The method of embodiment 60, having the formula:
Figure imgf000159_0001
Figure imgf000160_0001
 [0563] Embodiment 102 The method of embodiment 60, having the formula:
Figure imgf000161_0001
[0564] Embodiment 103. The method of embodiment 60, having the formula:
Figure imgf000161_0002
[0565] Embodiment 104. The method of embodiment 60, having the formula:
Figure imgf000161_0003
[0566] Embodiment 105. The method of embodiment 60, having the formula:
Figure imgf000161_0004
[0567] Embodiment 106. The method of embodiment 60, having the formula:
Figure imgf000161_0005
[0568] Embodiment 107. The method of embodiment 60, having the formula:
Figure imgf000161_0006
[0569] Embodiment 108. The method of embodiment 60, having the formula:
Figure imgf000161_0007
[0570] Embodiment 109. The method of embodiment 60, having the formula:
Figure imgf000162_0001
[0571] Embodiment 110. The method of embodiment 60, having the formula:
Figure imgf000162_0002
[0572] Embodiment 111. The method of embodiment 60, having the formula:
Figure imgf000162_0003
[0573] Embodiment 112. The method of embodiment 60, having the formula:
Figure imgf000162_0004
[0574] Embodiment 113. The method of embodiment 60, having the formula:
Figure imgf000162_0005
[0575] Embodiment 114. The method of embodiment 60, having the formula:
Figure imgf000163_0001
0576] Embodiment 115. The method of embodiment 60, having the formula:
Figure imgf000163_0002
[0577] Embodiment 116. A method of detecting the presence of α5β1 integrin or inhibiting α5β1 integrin activity, said method comprising contacting an α5β1 integrin with a compound having the formula:
Figure imgf000163_0003
wherein, R1 is independently halogen, -N3,
Figure imgf000163_0004
-OCXl 3,
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, -OSOviR1D, - HC(0) R1AR1B,
-N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-ORlc, -C(0) R1AR1B, -OR1D, - R1AS02R1D,
-NR1AC(0)R1C, - R1AC(0)ORlc, - R1AORlc, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary^L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C- independently halogen, -CX -CHX -CH2XZ, -OCX^ 3, - OCH2X2, -OCHX2 2, -CN, -SO^R20, -SOv2NR2AR2B, -NHC(0)NR2AR2B, -N(0)m2, -NR2AR2B, -C( 0)R2C, -C(0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C, -NR2AC(0)OR2C, 2 A 2C
-NR OR , -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is unsubstituted alkylene;
L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or
unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl ene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- - S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted
heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted
heteroarylene; R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or
substituted or unsubstituted heteroalkyl; R5 and R6 are independently hydi
Figure imgf000164_0001
Figure imgf000164_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, - CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ;R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH,
-NH2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, - HNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are
independently an integer from 0 to 3; ml, m2, vl and v2 are independently 1 or 2; zl is an integer from 0 to 5; and z2 is an integer from 0 to 9; and z3 is 0 or 1.
[0578] Embodiment 117. The method of embodiment 116, wherein said method comprises detecting the presence of α5β1 integrin and inhibiting α5β1 integrin activity.
[0579] Embodiment 118. The method of embodiment 116, wherein said method comprises detecting the presence of α5β1 integrin.
[0580] Embodiment 119. The method of embodiment 116, wherein said method comprises inhibiting α5β1 integrin activity.
V. EXAMPLES
[0581] The blockade of integrin alpha 5 beta 1 provides a novel target for the treatment of asthma. As shown in FIG. 1 A and IB, delivery of ATN-161, a low affinity yet specific inhibitor of alpha5betal, reduces the magnitude of airway narrowing in vivo in mice sensitized and challenged with ovalbumin, a widely used model of allergic asthma. In the same model, it was found that mice with a specific deletion of this integrin in smooth muscle also have reduced airway narrowing. The intracellular actin-myosin cross-bridging pathway serves as a useful target. Modulating the interactions of the cell and the extracellular matrix impairs the ability of the smooth muscle to transmit tension effectively. The blockade of integrin alpha 5 beta 1 was tested in vitro with human cell lines as well as in vivo with a mouse model of airway
hyperresponsiveness. Novel compounds as described herein, and identified in Table 1, have been synthesized and tested in vitro for their ability to inhibit cell adhesion mediated by either alpha5betal (adhesion of the colon carcinoma cell line SW480 to fibronectin, a response that is entirely dependent on binding of alpha5betal to fibronectin), or alphavbetal (adhesion of Chinese Hamster Ovary cells transfected with human alphav to the latency associated peptide of transforming growth factor beta, a response that is entirely dependent on binding of alphavbetal to LAP).
[0582] Table 1: Cell adhesion assay data
Figure imgf000166_0001
Figure imgf000167_0001
B: lOOnM to 10 uM; C: Greater than lOuM N/A: Not tested Example 1. Syntheses of Compounds HIJ-1016, HIJ-1017 and HIJ-1018
Figure imgf000168_0001
Figure imgf000168_0002
[0583] Step 1. Synthesis of 4-nitrophenyl carbamate: To a solution of mono-boc protected amine (5 mmol) and DIPEA (1.2eq) in DCM (lOmL) was added 4-nitrophenyl chloroformate (1.1 eq) dropwise at room temperature. The mixture was stirred for lh and diluted with DCM. The organic layer was washed with 1M HC1 and dried over Na2S04. The volatiles were removed under reduced pressure and the residue was purified by column chromatography (0 to 10 % MeOH in DCM) to yield a carbamate mixture of the following: tert-butyl (4-nitrophenyl) butane- 1,4-diyldicarbamate : yield 700 mg ( 37%), ESI-MS 376.6 (MNa+); tert-butyl (4-nitrophenyl) pentane-l,5-diyldicarbamate : yield 880 mg ( 45 %), ESI-MS 390.9 (MNa+); tert-butyl (4- nitrophenyl) hexane-l,6-diyldicarbamate : yield 700 mg ( 35%), ESI-MS 404.8 (MNa+).
[0584] Step 2. Synthesis of methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- aminopropanoate: To a solution of Fmoc- DAP (15.3 mmol) in 10% methanol in DCM (55 mL) was added TMS diazomethane (10 mL, 2M solution in hexanes) dropwise at room temperature. The mixture was stirred for 5 hours and the volatiles were removed under reduced pressure. The yellow residual oil was triturated with cold diethyl ether and filtered to yield the following white solid amine product: methyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- aminopropanoate : yield 3.1 g (60%), ESI-MS 341.7 (MH+).
[0585] Step 3. Urea synthesis: The carbamate mixture from step /, the amine product (lmmol) from step 2, and DIPEA (2 mmol) in THF (10 mL) was stirred for 3 hours at 60 °C. The volatiles were removed under reduced pressure and purified by column chromatography (0 to 10 % MeOH in DCM) to yield Fmoc protected amine products: methyl (S)-14-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2,2-dimethyl-4, l l-dioxo-3-oxa-5,10, 12-triazapentadecan-15-oate : yield (420 mg, 76 %) ESI-MS 577.8 (MNa+); methyl (S)-15-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2,2-dimethyl-4, 12-dioxo-3-oxa-5,l l, 13-triazahexadecan-16-oate : yield (530 mg, 93 %) ESI-MS 591.9 (MNa+); methyl (S)-16-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2,2-dimethyl-4, 13-dioxo-3-oxa-5,12, 14-triazaheptadecan-17-oate : yield (460 mg, 79%) ESI-MS 605.9 (MNa+).
[0586] Step 4. Deprotection of Fmoc protecting group: A solution of the Fmoc protected amine products from step 3 in 30% diethylamine in acetonitrile (15mL) was stirred for 1 hour and the volatiles were removed under reduced pressure and purified by column chromatography (0 to 20 %> MeOH in DCM) to yield Fmoc-deprotected amine products: methyl (S)-14-amino- 2,2-dimethyl-4,l l-dioxo-3-oxa-5,10, 12-triazapentadecan-15-oate : yield (200 mg, 79%), ESI-MS 355.8 (MNa ); methyl (S)-15 -amino-2,2-dimethyl-4,12-dioxo-3-oxa-5, l 1,13-triazahexadecan- 16-oate : yield (240 mg, 74%), ESI-MS 369.7 (MNa+); methyl (S)-16-amino-2,2-dimethyl-4,13- dioxo-3-oxa-5,12, 14-triazaheptadecan-17-oate : yield (190 mg, 67%), ESI-MS 361.8 (MH+).
[0587] Steps 5 and 6. Amidation with N-benzenesulfonyl-l-proline and deprotection of Boc protecting group: A solution of the Fmoc-deprotected amine products from step 4 and N- benzenesulfonyl-l-proline (1.1 eq), HCTU (1.05 eq) and DIPEA (2.2 eq) in DMF (0.2 M) was stirred for 3 hous at room temperature. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2S04 and concentrated under reduced pressure. A solution of 50%) TFA in DCM (5mL) was added to the crude residue and stirred for 2 hours. The volatiles were removed by a stream of nitrogen and precipitated by addition of cold diethyl ether. The ether was decanted after centrifuge and the crude mixture was used in the next step without further purification to yield the following amine products: methyl (S)-3-(3-(4- aminobutyl)ureido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoate : ESI-MS 470.6 (MH+); methyl (S)-3-(3-(5-aminopentyl)ureido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2- carboxamido)propanoate : ESI-MS 484.6 (MH+); methyl (S)-3-(3-(6-aminohexyl)ureido)-2-((S)- l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoate : ESI-MS 498.7 (MH+). [0588] Step 7. Syntheses of Compounds HIJ-1016, HIJ-1017, and HIJ-1018: To a solution of the amine products from steps 5 and 6 and DIPEA (6 eq) in DMF (3mL) was added Bis-Boc-IH- pyrazole-l-carboxamidine (2eq) and stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude mixture was treated with a solution of
TFA:T∑PS:H20 (95:2.5:2.5, 3mL) and stirred for 3 hours. The volatiles were blown off by a stream of nitrogen and lyophilized. The lyophilized powder was dissolved in a solution of THF:H20 (4: 1, 15mL) and stirred for 1.5 hours. The mixture was acidified by addition of a solution of 2M KHS04 and purified by RP-HPLC (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the following compound products were pooled and lyophilized: [HIJ-1016] : (S)-3-(3-(4-guanidinobutyl)ureido)-2-((S)-l- (phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time : 18.3 min, ESI-MS 498.9 (MH+); [HIJ-1017]: (S)-3-(3-(5-guanidinopentyl)ureido)-2-((S)-l- (phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time : 19.4 min, ESI-MS
512.8 (MH+); [HIJ-1018]: (S)-3-(3-(6-guanidinohexyl)ureido)-2-((S)-l- (phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time : 20.3 min, ESI-MS
526.9 (MH+).
Example 2. Synthesis of HIJ-1083
Figure imgf000170_0001
1 ) HCTU, DIPEA
Fmoc-aminohexanoic acid
2) diethylamine
3) Bis-Boc-1 H-pyrazole- 1 -carboxamidine, DIPEA
Figure imgf000170_0002
4) TFA/DCM
5) LiOH, THF/H20
[0589] Step 1. Synthesis of N-benzenesulfonyl-Pro-DAP-OMe: To a solution of N- benzenesulfonyl proline (10 mmol) in DMF (50 mL) were added DIPEA (2 eq) and HCTU (leq). After stirring 1 minute to obtain a clear solution, the amine shown in the above reaction scheme (10 mmol) in DMF (5 mL) was added to the mixture and stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with saturated NaHC03 solution and dried over Na2S04. After concentration under reduced pressure, the crude product was dissolved in 50% TFA (25 mL) in DCM and stirred for 2.5h. The volatiles were blown off by a stream of N2 and the residue was neutralized by addition of sat. Na2C03 solution. The product was extracted with DCM and dried over Na2S04 to yield the following amine product: methyl (S)-3-amino-2-((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoate : ESI-MS 356.7 (MH+). [0590] Step 2. Synthesis of HIJ-1083 : To stirred solution of Fmoc-aminohexanoic acid (1.1 eq), HCTU (1.1 eq) and DIPEA (2.2eq) was to the amine product (200mg) from step 1 at room temperature and stirred overnight. The mixture was diluted with ethyl acetate and washed with brine followed by drying over Na2S04. The mixture was concentrated under reduced pressure and diluted with 30 % diethylamine in acetonitrile. The mixture was stirred for 2 hours and the volatiles were removed under reduced pressure. The crude product was diluted with DMF (1 mL) and Bis-boc-lH-pyrazole-l-carboxamidine (2 eq) and DIPEA (2eq) were added at room temperature. The mixture was stirred overnight and diluted with ethyl acetate. The organic layer was washed with water and dried over Na2S04. After concentration under reduced pressure, the residue was dissolved in 50% TFA in DCM (5mL) and stirred for 1 hour. The volatiles were blown off by a stream of nitrogen and the residue was diluted with THF:H20 (4: 1, 5 mL). LiOH was added to the mixture to make the solution pH around 11 to 12. The mixture was stirred for lh and acidified by addition of 1M HC1 and purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield compound product HIJ-1083: (S)-3-(6-guanidinohexanamido)-2- ((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : 18. 7 min, ESI-MS 497.9 (MH+).
Example 3. Synthesis of HIJ-1093
Figure imgf000172_0001
[0591] Step 1. Synthesis of N-benzenesulfonyl-Pro-DAP-Gly-OMe: To a solution of N- benzenesulfonyl-Pro-DAP-OMe (712 mg) in DMF (5 mL) were added DIPEA (2.2 eq), Boc glycine (1.1 eq) and HATU (leq). The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with saturated NaHC03 solution and dried over Na2S04. After concentration under reduced pressure, the crude product was dissolved in 50% TFA in DCM (12 mL) and stirred lhour. The volatiles were removed by a stream of N2 and the crude product was diluted with DCM and washed with sat NaHC03 and 1M NaOH solution. After drying over Na2S04, the mixture was concentrated under reduced pressure to yield the amine product: methyl (S)-3-(2-aminoacetamido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2- carboxamido)propanoate : ESI-MS 413.6 (MH+).
[0592] Steps 2 and 3. Synthesis of N-benzenesulfonyl-Pro-DAP-Gly-Abz-OMe: To a solution of amine product from step 1 (300 mg) in DMF (3mL) was added Boc-aminobenzoic acid (leq), HCTU (leq) and DIPEA (2eq). The mixture was stirred overnight and diluted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude mixture was dissolved in 50% TFA in DCM (10 mL) and stirred for 1 hour. The volatiles were removed by a stream of N2 and diluted with DCM. The organic layer was washed with sat. Na2C03 solution and dried over Na2S04. After concentration under reduced pressure, half of the crude mixture (150mg, 1.25 eq), pyridine N- oxide (19 mg, 1 eq), DIPEA (0.125 mL, 3.75eq) were dissolved in DCM and PyBroP (120mg, 1.3eq) was added at room temperature. The mixture was stirred overnight and washed with water. The organic layer was concentrated and dissolved in THF:H20 (4: 1, 5 mL). LiOH (21 mg) was added to the mixture and acidified with 1M HC1 after stirring for 3h at room temperature. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1093: methyl (S)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2- carboxamido)-3-(2-(3-(pyridin-2-ylamino)benzamido)acetamido)propanoate: retention time 19.0 min, ESI-MS 595.9 (MH+). Example 4. Synthesis of HIJ-1094
Figure imgf000173_0001
Figure imgf000173_0002
[0593] A mixture of half of the crude amine (150mg, 1.25 eq) from synthesis of HIJ-1093 (Example 3), Bis-boc-lH-pyrazole- 1-carboxamidine (2eq), DIPEA (2eq) in DMF (lmL) was stirred overnight at room temperature. The mixture was diluted with DCM and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in 50% TFA in DCM. The mixture was stirred for 2 hours and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (4: 1, 5mL) and LiOH was added until the solution pH became app. 11 to 12. After stirring 1 hour at room temperature, the mixture was acidified with 1M HCl. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1094: (S)-3-(2-(3-guanidinobenzamido)acetamido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2- carboxamido)propanoic acid: retention time 17.9 min, ESI-MS 560.9 (MH+).
Example 5. Synthesis of HIJ-1099
Figure imgf000174_0001
Figure imgf000174_0002
[0594] Step 1. Synthesis of N-benzenesulfonyl-Pro-DAP-azaGly-OMe: To a mixture of amine (600 mg, 1 eq) andl -(tert-butyl) 2-(4-nitrophenyl) hydrazine- 1,2-dicarboxylate (leq) in anhydrous DCM (4mL) was added trimethylamine (leq) at room temperature, as indicated in the above scheme. The mixture was stirred 1 hour at room temperature. The mixture was diluted with DCM and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was dissolved in 50% TFA in DCM. The mixture was stirred for 1 hour and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in DCM again and washed with sat Na2C03 solution and dried over Na2S04. The organic layer was concentrated under reduced pressure to yield the amine product: methyl (S)-3- (hydrazinecarboxamido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoate : ESI- MS 414.6 (MH+).
[0595] Steps 2 and 3. Synthesis of HU-1099: To a solution of the amine product (200 mg) from step 1 in DMF (2 mL) was added Boc-aminobenzoic acid (1.2 eq), HCTU (1.2 eq) and DIPEA (2.5eq). The mixture was stirred overnight and diluted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude mixture was dissolved in 50% TFA in DCM (5 mL) and stirred for 1 hour. The volatiles were removed by a stream of N2 and diluted with DCM. The organic layer was washed with sat. Na2C03 solution and dried over Na2S04. The mixture was concentrated under reduced pressure and dissolved in DMF (2mL). Bis-boc-lH-pyrazole-1- carboxamidine (2eq) and DIPEA (2eq) were added to the mixture and stirred overnight at room temperature. The mixture was diluted with ethyl acetate (50mL) and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in 50% TFA in DCM. The mixture was stirred for 2h and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (4: 1, 5mL) and LiOH was added until the solution pH became app. 11 to 12. After stirring lh at room temperature, the mixture was acidified with 1M HCl. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1%) TFA in 99 %> acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1099: (S)-3-(2-(3-guanidinobenzoyl)hydrazine- l-carboxamido)-2-((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time 17.6 min ESI-MS 561.9 (MH+).
Example 6. Synthesis of HIJ-1203
Figure imgf000176_0001
Figure imgf000176_0002
[0596] To a solution of amine (255 mg, TFA salt) in DMF (4 mL) was added Boc-glycine (1 eq), HCTU (0.95 eq) and DIPEA (4 eq) as indicated in the above reaction scheme. The mixture was stirred overnight and diluted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude mixture was dissolved in 30% diethylamine in acetonitrile (6 mL) and stirred for 1 hour. The volatiles were removed under reduced pressure and the layer was separated by addition hexanes. The lower yellow layer was collected and the washing was repeated twice. The crude amine was diluted with DMF (2mL) and a premixed solution of acid (89 mg), HATU (114mg), and DIPEA (0.104 mL) in DMF (2mL) was added and stirred overnight. The reaction mixture was then diluted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude product was dissolved in 50% TFA in DCM (5mL) and stirred for 3h. The volatiles were blown off by a stream of nitrogen. The oily residue was then precipitated by addition cold diethyl ether. After centrifuge, the supernatant was decanted. The solid was then dissolved in DMF (2mL) and Boc- 3-aminobenzoic acid (71mg), HATU (114mg), DIPEA (0.174 mL) were added and stirred overnight. The reaction mixture was then diluted with ethyl acetate. The organic layer was washed with water and brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude product was then dissolved in 50% TFA in DCM (5mL). The mixture was stirred for 2 hours and the volatiles were removed by a stream of nitrogen. The oily residue was then dissolved in ethyl acetate and washed with sat. Na2C03 solution. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in DMF (ImL). Bis-boc-lH-pyrazole-l-carboxamidine (0.5mmol) and DIPEA (0.5mmol) were added to the mixture and stirred overnight at room temperature. The mixture was diluted with ethyl acetate (30mL) and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in 50% TFA in DCM (5mL). The mixture was stirred for 2 hours and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (4: 1, 5mL) and LiOH was added until the solution pH became app. 11 to 12. After stirring 1 hour at room temperature, the mixture was acidified with 1M HC1. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1203: (2S)-3-(2-(3-guanidinobenzamido)acetamido)-2-(2-(phenylsulfonyl)-2- azabicyclo[2.2.2]octane-3-carboxamido)propanoic acid : retention time 15.8 min ESI-MS 600.8 (MH+).
xample 7. Synthesis of HIJ-1204
Figure imgf000178_0001
[0597] To the amine (0.087 mmol) was added 2-methylthioimidazoline (lmmol) in DMF was added DIPEA (2mmol) and stirred at 135 °C bath for 2 hours. The mixture was cooled down and water was added. The mixture was extracted with ethyl acetate. The volatiles were removed under reduced pressure and the crude residue was dissolved in DMF-H20 (1 : 1, 2mL). LiOH (50mg) was added and stirred at room temperature for 3 hours and the mixture was acidified (pH=4) by 1M HCl and lyophilized. The lyophilized mixture was purified by RP-HPLC.
(Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ- 1204:(2S)-2-(2-(phenylsulfonyl)-2-azabicyclo[2.2.2]octane-3-carboxamido)-3-(2-(3-((4,4',5,5'- tetrahydro-l'H-[l,2'-biimidazol]-2-yl)amino)benzamido)acetamido)propanoic acid : retention time 16.0 min ESI-MS 695.1 (MH+).
Example 8. Synthesis of HIJ-1213
Figure imgf000179_0001
[0598] To a mixture of amine (2mmol, TFA salt) and Fmoc-Lys(alloc)-OH (leq), DIPEA (5eq) was added HATU (leq) and stirred overnight. The mixture was diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was dissolved in 30% diethylamine in acetonitrile (15mL) and stirred for 1 hour. The volatiles were removed under reduced pressure and the layer was separated by addition hexanes. The lower yellow layer was collected and the washing was repeated twice. The crude amine was diluted with DMF (lOmL) and Boc-aminovaleric acid (2 mmol), HATU (1.9 mmol), and DIPEA (4 mmol) were added. The mixture was stirred overnight. The reaction mixture was then diluted with ethyl acetate. The organic layer was successively washed with 1M HCl, sat. NaHC03 solution, brine and dried over Na2S04. The mixture was concentrated under reduced pressure. The crude product was dissolved in 50% TFA in DCM (lOmL) and stirred for 3 hours. The volatiles were blown off by a stream of nitrogen. The oily residue was then precipitated by addition cold diethyl ether. After centrifuge, the supernatant was decanted. The solid was dissolved in DMF (lOmL) and Bis-boc-lH-pyrazole-1- carboxamidine (0.5mmol) and DIPEA (0.5mmol) were added to the mixture. After stirring overnight at room temperature, the mixture was diluted with ethyl acetate (50mL) and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in 50% TFA in DCM (lOmL). The mixture was stirred for 2 hours and the volatiles were removed by a stream of nitrogen. The crude product was precipitated by addition of cold ether. After centrifuge, the supernatant was decanted. The solid was dissolved in THF:H20 (4: 1, lOmL) and LiOH (87mg) was added After stirring 1 hour at room temperature, the mixture was acidified with 1M HCl. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 70 % B over 37 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1%) TFA in 99 %> acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1213: (13S,17S)-13-(4- (((allyloxy)carbonyl)amino)butyl)-5, l l,14-trioxo-17-((S)-l-(phenylsulfonyl)pyrrolidine-2- carboxamido)-4-oxa-6, 12, 15-triazaoctadec-l-en-18-oic acid : retention time 24.8 min ESI-MS 695.9 (MH+).
Example 9. Synthesis of HIJ-1216
Figure imgf000180_0001
[0599] To a mixture of ΗΠ-1213 (Example 8) (2 mg, TFA salt) in THF (2mL) was added dimedone (4mg) and Pd(PPh3)4 (4mg). After 1 hour, H20 (lmL) was added and additional Pd(PPh3)4 was added. After 3 hours, FITC (25mg) and DIPEA (0.066 mL) were added and stirred overnight. The solvent was removed and purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 55 % B over 14 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1%> TFA in 99 %> acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1216: 5-(3-((S)-6-(((S)-2-carboxy-2- ((S)-l-(phenylsulfonyl)pyrrolidine-2-carboxamido)ethyl)amino)-5-(5-guanidinopentanamido)-6- oxohexyl)thioureido)-2-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)benzoic acid :
retention time 19.6 min ESI-MS: 1001.1 (M+). Example 10. Synthesis of HIJ-1437
Figure imgf000181_0001
[0600] 3,5-diaminobenzoic acid (lOmmol) was suspended in DCM/MeOH (2/1, 30mL) and TMSdiazomethane (6 mL, 2M in hexanes) was added to the stirring mixture dropwise. After stirring for 1 hour, the volatiles were removed under reduced pressure. DMF (lOmL) was added to the oily residue and Bis-Boc-lH-pyrazole-l-carboxamide (2g) was added. After 20 min, NaOH solution (1M) was added to make the solution basic (pH=10) and the aqueous layer was extracted with ethyl acetate. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude amine was dissolved in DMF (15 mL) and Boc-aminobutyric acid (660mg), DIPEA (1.2 mL), HATU (1.14g) were added. The mixture was stirred overnight and diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/ethyl acetate as eluants. (ESI-MS; 594.6 (MH+)). Thus obtained ester (350mg) was dissolved in THF:H20 (3 : 1, lOmL). Then 3M NaOH (0.7 mL) and a small amount of MeOH were added and stirred 1 hour. The reaction mixture was diluted with ethyl acetate and acidified with 1M HC1. The organic layer was dried over Na2S04 and concentrated under reduced pressure. The crude acid was dissolved in DMF (5mL) and Benzenesulfonyl-L-Pro-Gly-OMe (145mg), HATU (100 mg), DIPEA (0.121mL) were added and stirred overnight. The mixture was diluted with ethyl acetate (30mL) and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and dissolved in 50% TFA in DCM (15mL). The mixture was stirred for 2h and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (4: 1, 5mL) and LiOH (55mg) was added. After stirring 1 hour at room temperature, the mixture was acidified with 1M HCl. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B : 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1437: (S)-3-(2-(3-(4-aminobutanamido)-5-guanidinobenzamido)acetamido)-2-((S)-l- (phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time 17.1 min, ESI-MS: 660.6 (MH+). Example 11. Synthesis of HIJ-1483
Figure imgf000182_0001
HATU, DIPEA
4) NaOH, THF/H20
Figure imgf000182_0002
[0601] To a solution of amine (777mg) in DMF(5mL) were added Fmoc-aminobutyric acid (leq), DIPEA (2.5eq), and HATU (leq) and stirred overnight. The mixture was diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was dissolved in 30% diethylamine in acetonitrile
(40mL) and stirred for 2 hours. The volatiles were removed under reduced pressure and the layer was separated by addition hexanes (lOOmL). The lower yellow layer was collected and the washing was repeated twice. To the crude amine (600mg) in DMF (15 mL) were added 1- amantane carboxylic acid (leq), HATU (leq), DIPEA (2. leq) and stirred overnight. The mixture was diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/ethyl acetate as eluants. To the above ester (120mg) in THF-H20 (4: 1, 5mL) was added NaOH (200 mg) and stirred overnight. THF was removed under reduced pressure and the solution was acidified to pH=4 by 2M KHS04. The solid precipitated, filtered and washed with water and lyophilized. To the acid (65 mg) in DMF (lmL) was added benzenesulfonyl-L-Pro-DAP-Gly-OMe (52mg), HATU (38mg), and DIPEA (0.07mL). The mixture was stirred overnight and diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and then dissolved in 50% TFA in DCM (5mL). The mixture was stirred for 3h and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (4: 1, 5mL) and LiOH (24mg) was added. After stirring 3h at room temperature, the mixture was acidified with 2M KHS04. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1483: (2S)-3-(2-(3-(4-((ls,3s)-adamantane-l- carboxamido)butanamido)-5-guanidinobenzamido)acetamido)-2-((S)-l- (phenylsulfonyl)pyrrolidine-2-carboxamido)propanoic acid : retention time 20.7 min, ESI-MS: 822.7 (MH+). Exam le 12. Synthesis of HIJ-1491
Figure imgf000183_0001
[0602] To a solution of amine (307mg) in DMF(5mL) were added octanoic acid (leq), DIPEA (2.5eq), and HATU (leq) and stirred overnight. The mixture was diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using hexanes/ethyl acetate as eluants. To the above ester (53 mg) in THF-H20 (3 : 1, 5mL) was added NaOH (60 mg) and and EtOH (2mL) and stirred overnight. THF was removed under reduced pressure and diluted with ethyl acetate. The solution was acidified to pH=2 by 2M KHS04. The organic layer was dried over Na2S04 and concentrated under reduced pressure. To the crude acid in DMF (lmL) was added benzenesulfonyl-L-Pro-DAP-Gly-OMe (50mg), HATU (38mg), and DIPEA
(0.07mL). The mixture was stirred for 72 hours and diluted with ethyl acetate and washed with water. After drying over Na2S04, the mixture was concentrated under reduced pressure and then dissolved in 50% TFA in DCM (4mL). The mixture was stirred for 3 hours and the volatiles were removed by a stream of nitrogen. The oily residue was dissolved in THF:H20 (3 : 1, 6mL) and LiOH (32mg) was added. After stirring 3 hours at room temperature, the mixture was acidified with 2M KHS04. The mixture was purified by RP-HPLC. (Atlantis Prep T3 OBD 19x150 mm, 5 % to 65 % B over 23 min, flow rate : 10 ml/min, solvent A: 0.1% TFA in H20, solvent B: 0.1% TFA in 99 % acetonitrile in H20) . The fractions containing the product were pooled and lyophilized to yield the compound product HIJ-1491: (S)-3-(2-(3-guanidino-5- octanamidobenzamido)acetamido)-2-((S)-l -(phenyl sulfonyl)pyrrolidine-2- carboxamido)propanoic acid : retention time 20.8 min, ESI-MS: 701.5 (MH+).

Claims

WHAT IS CLAIMED IS:
1. A com ound having the formula:
Figure imgf000185_0001
wherein,
independently halogen, -N3,
Figure imgf000185_0002
-CH2X1, -OCX1
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, -OSOviR1D, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D,
- R1AC(0)R1C, - R1AC(0)ORlc, - R1A0R1C, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX2 2, -CN, -SO^R20, -SOv2NR2AR2B, -NHC (0)NR2AR2B , -N(0)m2, -NR2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C,
-NR2AC(0)OR2C, -NR2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is unsubstituted alkyl ene;
L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkyl ene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene;
R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene;
R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R5 and R6 are independently hydrogen,
Figure imgf000186_0001
Figure imgf000186_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -O H2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CO H2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsub stituted heteroaryl ;
each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 3;
ml, m2, vl and v2 are independently 1 or 2;
zl is an integer from 0 to 5;
z2 is an integer from 0 to 9; and
z3 is 0 or 1 ;
with the proviso that when R5 is hydrogen R6 is not hydrogen.
The com ound according to claim 1 having the formula:
Figure imgf000187_0001
wherein,
R1 is independently halogen, -CX ,
Figure imgf000187_0002
-OCXl 3, -
Figure imgf000187_0003
-CN, -SO„iR1D, -SOviNR1AR1B, -NHC(0)NR1AR1B, -N(0)mb -NR1AR -C(0)R1C, -C(0)-ORlc, -C(0)NR1AR1B, -OR1D, -NR1AS02R1D, -NR1AC(0)R1C, -NR1AC(0)0
1C 1A 1C
R , -NR OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX22, -CN, -SO„2R2D, -SOv2 R2AR2B, - HC(0) R2AR2B, -N(0)m2, -NR2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0) R2AR2B, -OR2D, - R2AS02R2D, - R2AC(0)R2C, -NR2AC(0)OR2C, -NR OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety;
R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CONH2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is unsubstituted alkylene;
L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene;
R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
L4 is -0-, -S-, -N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or
unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaryl ene; R is hydrogen, -CN, -COOH, -CX 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R5 and R6 are independently hydrogen,
Figure imgf000189_0001
NR10
^ NH2
, ^ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsub stituted heteroaryl ;
each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 4;
ml, m2, vl and v2 are independently 1 or 2; 75 zl is an integer from 0 to 5; and
76 z2 is an integer from 0 to 9;
77 with the proviso that when R5 is hydrogen R6 is not hydrogen.
1 3. The compound of claim 1, wherein zl is an integer from 1 to 5.
1 4. The compound of claim 1, wherein zl is 0.
1 5. The compound of claim 1, wherein Y is -C-C-, -C=C-, -0-C-, -C-0-,
2 C-0-C-,-C-S-, -S-C, or -C-S-C-.
The compound of claim 1, wherein
Figure imgf000190_0001
has the formula
Figure imgf000190_0002
The compound of claim 1, having the formula:
Figure imgf000190_0003
1 8. The compound of claim 1, wherein L1 is a bond.
1 9. The compound of claim 1, wherein R1 is independently halogen, -N3,
2 CF3, -CCI3, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH,
3 -CO H2, -SH, -SO2, -S02CH3 -S03H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2,
4 substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or
5 unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
6 unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.
1 10. The compound of claim 1, wherein R1 is independently
2 halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. 11. The compound of claim 1, wherein L2 is unsubstituted Ci-C2 alkylene. 12. The compound of claim 1, wherein L2 is unsubstituted methylene. 13. The compound of claim 1, wherein R4 is hydrogen. 14. The compound of claim 1, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkyl ene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene. 15. The compound of claim 1, wherein L3 is a bond. 16. The compound of claim 1, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 17. The compound of claim 1, wherein L3 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene. 18. The compound of claim 1, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene. 19. The compound of claim 1, wherein L3 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene. 20. The compound of claim 1, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered
heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene.
21. The compound of claim 1, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 22. The compound of claim 1, wherein L4 is substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene. 23. The compound of claim 1, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene. 24. The compound of claim 1, wherein L4 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene. 25. The compound of claim 1, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. 26. The compound of claim 1, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. 27. The compound of claim 1, wherein L4 is unsubstituted phenylene. 28. The compound of claim 1, wherein R5 and R6 are independently
hydrogen,
Figure imgf000192_0001
, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 29. The compound of claim 1, wherein R5 and R6 are independently
hydrogen,
Figure imgf000192_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. 30. The compound of claim 1, wherein R5 is substituted or unsubstituted 5 to 6 membered heteroaryl.
31. The compound of claim 1, wherein R6 is substituted or unsubstituted 5 to 6 membered heteroaryl. 32. The compound of claim 1, wherein R5 and R6 are independently
hydrogen,
Figure imgf000193_0001
33. The compound of claim 1, wherein R5 is hydrogen and R6 is
Figure imgf000193_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl. 34. The compound of claim 1, wherein R5 is hydrogen and R6 is
Figure imgf000193_0003
, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 35. The compound of claim 1, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 36. The compound of claim 1, wherein R5 is hydrogen and R6 is
NR10
¾^NHR9 37. The compound of claim 1, wherein R5 is hydrogen and R6 is
Figure imgf000193_0004
38. The compound of claim 1, wherein R5 is hydrogen and R6 is substituted or unsubstituted heteroaryl.
39. The compound of claim 1, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl.
40. The compound of claim 1, wherein R3 is hydrogen.
41. The compound of claim 1, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
The compound of claim 1, having the formula:
Figure imgf000194_0001
Figure imgf000195_0001
193
Figure imgf000196_0001
The compound of claim 1, having the formula:
Figure imgf000196_0002
The compound of claim 1, having the formula:
Figure imgf000196_0003
The compound of claim 1, having the formula:
Figure imgf000196_0004
The compound of claim 1, having the formula:
Figure imgf000196_0005
The compound of claim 1, having the formula:
Figure imgf000197_0001
48. The compound of claim 1, having the formula:
Figure imgf000197_0002
The compound of claim 1, having the formula:
Figure imgf000197_0003
The compound of claim 1, having the formula:
Figure imgf000197_0004
51. The compound of claim 1, having the formula:
Figure imgf000197_0005
The compound of claim 1, having the formula:
Figure imgf000197_0006
The compound of claim 1, having the formula:
Figure imgf000197_0007
The compound of claim 1, having the formula:
Figure imgf000198_0001
The compound of claim 1, having the formula:
Figure imgf000198_0002
The com ound of claim 1, having the formula:
Figure imgf000198_0003
The compound of claim 1, having the formula:
Figure imgf000199_0001
59. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 55. 60. A method for treating asthma, said method comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the formula:
Figure imgf000199_0002
wherein,
R1 is independently halogen, -N3, -CX , -CHX^, -CH2X1, -OCXS,
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, -OSOviR1D, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D,
- R1AC(0)R1C, - R1AC(0)ORlc, - R1A0R1C, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, - OCH2X2, -OCHX2 2, -CN, -SO^R20, -SOv2NR2AR2B, -NHC (0)NR2AR2B , -N(0)m2, -NR2AR2B, -C(0)R , -C(0)-OR , -C(0)NR2AR , -OR , -NR2AS02R , -NR2AC(0)R , -NR2AC(0)0 R2C, - R2AOR2C, -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety;
R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CO H2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is unsubstituted alkyl ene;
L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;
R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R5 and R6 are independently hydrogen,
Figure imgf000200_0001
NR10
^ NH2
, ^ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, - H2, -COOH, -CO H2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CONH2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 3;
ml, m2, vl and v2 are independently 1 or 2;
zl is an integer from 0 to 5;
z2 is an integer from 0 to 9; and
z3 is 0 or l . 61. The method of claim 60, wherein zl is an integer from 1 to 5. 62. The method of claim 60, wherein Y is -C-C-, -C=C-, -0-C-, -C-0-, -C- 0-C-,-C-S-, -S-C, or -C-S-C-. The method of claim 60, wherein
Figure imgf000202_0001
has the formula
Figure imgf000202_0002
The method of claim 60 having the formula:
Figure imgf000202_0003
65. The method of claim 60, wherein L1 is a bond. 66. The method of claim 60, wherein R1 is independently halogen, -N3, - CF3, -CCI3, -CBr3, -CI3, -CN, -CHO, -OH, - H2, -COOH, -CO H2, -SH, -S02, -S02CH3 - S03H, -OS03H, -S02 H2, - HNH2, -O H2, - HC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety. 67. The method of claim 60, wherein R1 is independently
halogen, -OMe, -SMe, -S02Me, -S02Ph, -COOH, substituted or unsubstituted Ci-C8 alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.
68. The method of claim 60, wherein L is unsubstituted Ci-C2 alkylene.
69. The method of claim 60, wherein L2 is unsubstituted methylene. 70. The method of claim 60, wherein R4 is hydrogen. 71. The method of claim 60, wherein L3 is a bond, substituted or unsubstituted Ci-C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkyl ene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. 72. The method of claim 60, wherein L3 is a bond. 73. The method of claim 60, wherein L3 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 74. The method of claim 60, wherein L3 is substituted or unsubstituted Ci- C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene. 75. The method of claim 60, wherein L3 is substituted or unsubstituted 2 to 8 membered heteroalkylene. 76. The method of claim 60, wherein L3 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene. 77. The method of claim 60, wherein L4 is substituted or unsubstituted Ci- C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered
heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene. 78. The method of claim 60, wherein L4 is substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 79. The method of claim 60, wherein L4 is substituted or unsubstituted Ci- C8 alkylene, or substituted or unsubstituted 2 to 8 membered heteroalkylene. 80. The method of claim 60, wherein L4 is substituted or unsubstituted 2 to 8 membered heteroalkylene.
81. The method of claim 60, wherein L4 is an oxo- substituted Ci-C8 alkylene, or oxo- substituted 2 to 8 membered heteroalkylene. 82. The method of claim 60, wherein L4 is substituted or unsubstituted arylene, or substituted or unsubstituted heteroaryl ene. 83. The method of claim 60, wherein L4 is substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroaryl ene. 84. The method of claim 60, wherein L4 is unsubstituted phenylene. 85. The method of claim 60, wherein R5 and R6 are independently
hydrogen,
Figure imgf000204_0001
, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 86. The method of claim 60, wherein R5 and R6 are independently
hydrogen,
Figure imgf000204_0002
, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. 87. The method of claim 60, wherein R5 is substituted or unsubstituted 5 to 6 membered heteroaryl. 88. The method of claim 60, wherein R6 is substituted or unsubstituted 5 to 6 membered heteroaryl. 89. The method of claim 60, wherein R5 and R6 are independently
hydrogen,
Figure imgf000204_0003
90. The method of claim 60, wherein R5 is hydrogen and R6 is
Figure imgf000205_0001
,
Figure imgf000205_0002
, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
91. The method of claim 60, wherein R5 is hydrogen and R6 is
Figure imgf000205_0003
,
Figure imgf000205_0004
, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 92. The method of claim 60, wherein R5 and R6 are joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. 93. The method of claim 60, wherein R5 is hydrogen and R6 is
NR10
¾ NHR9
94. The method of claim 60, wherein R5 is hydrogen and R6 is
Figure imgf000205_0005
95. The method of claim 60, wherein R5 is hydrogen and R6 is substituted or unsub stituted heteroaryl . 96. The method of claim 60, wherein R5 is hydrogen and R6 is substituted or unsubstituted 5 to 6 membered heteroaryl. 97. The method of claim 60, wherein R3 is hydrogen.
98. The method of claim 60, wherein R3 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
The method of claim 60, having the formula:
Figure imgf000206_0001
Figure imgf000207_0001
205
Figure imgf000208_0001
The method of claim 60, having the formula:
Figure imgf000208_0002
The method of claim 60, having the formula:
Figure imgf000208_0003
The method of claim 60, having the formula:
Figure imgf000208_0004
The method of claim 60, having the formula:
Figure imgf000208_0005
The method of claim 60, having the formula:
Figure imgf000208_0006
The method of claim 60, having the formula:
Figure imgf000208_0007
The method of claim 60, having the formula:
Figure imgf000209_0001
The method of claim 60, having the formula:
Figure imgf000209_0002
The method of claim 60, having the formula:
Figure imgf000209_0003
The method of claim 60, having the formula:
Figure imgf000209_0004
1 1. The method of claim 60, having the formula:
Figure imgf000209_0005
12. The method of claim 60, having the formula:
Figure imgf000210_0001
Figure imgf000210_0002
Figure imgf000210_0003
115. The method of claim 60 having the formula:
Figure imgf000210_0004
116. A method of detecting the presence of α5β1 integrin or inhibiting α5β1 integrin activity, said method comprising contacting an α5β1 integrin with a compound having the formula:
Figure imgf000211_0001
wherein,
independently halogen, -N3, -CX , -CHX^, -CH2X1, -OCX1
-OCH2X1, -OCHX^, -CN, -SO„iR1D, -SOvi R1AR1B, -OSOviR1D, - HC(0) R1AR1B, -N(0)mi, - R1AR1B, -C(0)R1C, -C(0)-0R1C, -C(0) R1AR1B, -OR1D, - R1AS02R1D,
- R1AC(0)R1C, - R1AC(0)ORlc, - R1A0R1C, -O H2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L1 is a bond or substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
Y is a bond, -C-, -C-C-, -C=C-, -C-C-C-, -C=C-C-, -C-C=C-, -0-C-, -C-0-, -C-O-C, -S-C-, -C-S-,or -C-S-C-;
R2 is independently halogen, -CX2 3, -CHX2 2, -CH2X2, -OCX2 3, -OCH2X2, -OCHX2 2, -CN, -SO„2R2D, -SOv2NR2AR2B, -NHC(0)NR2AR2B, -N(0)m2, -NR2AR2B, -C(0)R2C, -C(0)-OR2C, -C(0)NR2AR2B, -OR2D, -NR2AS02R2D, -NR2AC(0)R2C, -NR2AC(0)OR2C, -NR 2 A OR 2C , -S02Ph, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a prodrug moiety; R4 is independently hydrogen, -CX4 3, -CN, -COOH, -CO H2, -CHX4 2, -CH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is unsubstituted alkyl ene;
L3 is a bond, -0-, -S-, -N(R7)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkyl ene, substituted or unsubstituted cycloalkyl ene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R7 is hydrogen, -CN, -COOH, -CX7 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
L4 is -0-, -S-,-N(R8)-, -C(O)-, C(0)0- -S(O) -, -S(0)2- substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene;
R8 is hydrogen, -CN, -COOH, -CX8 3, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R5 and R6 are independently hydrogen,
Figure imgf000212_0001
NR10
^ NH2
, , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 and R6 may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R9 is hydrogen, halogen, -N3, -CX9 3, -CHX9 2, -CH2X9, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -ONH2, -NHC(0)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R10 is hydrogen, halogen, -N3, -CX10 3, -CHX10 2, -CH2X10, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -S02, -S02CH3 -S03H, -S04H, -S02NH2, -NHNH2, -O H2, - iC(0) HNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, is independently
hydrogen, -CX3, -CN, -COOH, -CO H2, -CHX2, -CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
each X, X1, X2, X4, X7, X8, X9, and X10 are independently -F, -CI, -Br, or -I; nl and n2 are independently an integer from 0 to 3;
ml, m2, vl and v2 are independently 1 or 2;
zl is an integer from 0 to 5; and
z2 is an integer from 0 to 9; and
z3 is 0 or l . 117. The method of claim 116, wherein said method comprises detecting the presence of α5β1 integrin and inhibiting α5β1 integrin activity. 118. The method of claim 116, wherein said method comprises detecting the presence of α5β1 integrin.
119. The method of claim 116, wherein said method comprises inhibiting α5β1 integrin activity.
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